Local precise drug delivery is conducive to improving therapeutic efficacy and minimizing off-target toxicity.Current local delivery approaches are focused mostly on superficial or postoperative tumor lesions,due to t...Local precise drug delivery is conducive to improving therapeutic efficacy and minimizing off-target toxicity.Current local delivery approaches are focused mostly on superficial or postoperative tumor lesions,due to the challenges posed by the inaccessibility of deep-seated tumors.Herein,we report a magnetic continuum soft robot capable of non-invasive and site-specific delivery of prodrug nanoassemblies-loaded hydrogel.The nanoassemblies are co-assembled from redox-responsive docetaxel prodrug and oxaliplatin prodrug,and subsequently embedded into a hydrogel matrix.The hydrogel precursor and crosslinker are synchronously delivered using the soft robot under magnetic guidance and in situ crosslinked at the gastric cancer lesions,forming a drug depot for sustained release and long-lasting treatment.As the hydrogel gradually degrades,the nanoassemblies are internalized by tumor cells.The redox response ability enables them to be selectively activatedwithin tumor cells to trigger the release of docetaxel and oxaliplatin,exerting a synergistic anti-tumor effect.We find that the combination effectively induces immunogenic cell death of gastric tumor,enhancing antitumor immune responses.This strategy offers an intelligent and controllable integration platform for precise drug delivery and combined chemo-immunotherapy.展开更多
Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during c...Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.展开更多
Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strong...Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.展开更多
Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell ...Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.展开更多
Metastasis and heterogeneity pose major challenges in cancer treatment.Although chemoimmunotherapy shows promising efficacy,its therapeutic impact is limited by off-target effects and differences in the delivery sites...Metastasis and heterogeneity pose major challenges in cancer treatment.Although chemoimmunotherapy shows promising efficacy,its therapeutic impact is limited by off-target effects and differences in the delivery sites of chemotherapeutic drugs and immunosuppressants.In this study,an engineered platelets(Pts)-based nano-aircraft,Pts@DOX/HANGs@Gal,was constructed with an internally loaded chemotherapeutic drug,doxorubicin,and externally grafted reduction-responsive hyaluronidase-cross-linked nanospheroids loaded with the immunosuppressant galunisertib for precise tumor chemo-immunotherapy.The normal physiological features of host Pts,including their excellent targeting capability for both metastatic and orthotopic tumors,are not disturbed by functional nanosystems.The interaction between Pts@DOX/HANGs@Gal and tumors gives rise to Pts activation,achieving the continuous targeted delivery of DOX to tumors,inducing the transition from cold to hot tumors,and promoting the recruitment of immune cells.Simultaneously,the external nanospheres disintegrate from Pts@DOX/HANGs@Gal,releasing galunisertib and hyaluronidase into the extracellular matrix to relieve immune tolerance and open up a high-speed channel for the tumor infiltration of immune cells and deep tumor penetration of the nanosystem.Consequently,Pts@DOX/HANGs@Gal not only effectively reinforced the antitumor immune response through self-recognized tumor-targeting chemo-immunotherapy and graded drug delivery but also reduced tumor metastasis in vivo.This study presents promising Pt-based nanovesicles for precise cancer treatment.展开更多
Background:Intrahepatic cholangiocarcinoma(ICC)is a challenging can-cer with an increasing incidence.The Phase III TOPAZ-1/KEYNOTE-966study demonstrated chemo-immunotherapy(CIT)as a significant advance-ment,potentiall...Background:Intrahepatic cholangiocarcinoma(ICC)is a challenging can-cer with an increasing incidence.The Phase III TOPAZ-1/KEYNOTE-966study demonstrated chemo-immunotherapy(CIT)as a significant advance-ment,potentially replacing traditional chemotherapy for advanced biliary tractcancer.Ferroptosis is a crucial process that affects cancer cell survival andtherapy resistance.Although AKT hyperactivation is prevalent in numerouscancers,including ICC,its role in ferroptosis resistance remains unclear.Thisstudy explored whether targeting ferroptosis can enhance CIT response rates,specifically in ICC patients with AKT hyperactivation.Methods:In vivo metabolic CRISPR screening in a KrasG12D/Tp53−/−ICCmouse model was used to identify primary regulators of ferroptosis duringCIT(gemcitabine,cisplatin,and anti-mouse programmed cell death 1 ligand 1).Phosphoenolpyruvate carboxykinase 1(PCK1)was assessed for its role in fer-roptosis and treatment resistance in preclinical models under AKT activationlevels.Molecular and biochemical techniques were used to explore PCK1-relatedresistance mechanisms in AKT-hyperactivated ICC.Results:Under AKT hyperactivation condition,phosphorylated PCK1(pPCK1)promoted metabolic reprogramming,enhancing ubiquinol and menaquinone-4synthesisthrough the mevalonate(MVA)pathway.This cascade was mediated bythe pPCK1-pLDHA-SPRINGlac axis.Inhibiting PCK1 phosphorylation or usingsimvastatin significantly augmented CIT efficacy in preclinical models.Clini-cal data further indicated that phosphorylated AKT(pAKT)-pPCK1 levels mightserve as a biomarker to predict CIT response in ICC.Conclusion:Thisstudy identified the pAKT-pPCK1-pLDHA-SPRINGlac axis asa novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC byassociating glycolytic activation with MVA flux reprogramming.Targeting thisaxis,potentially through statin-based therapies,may offer a strategy to sensitizeICC cells to ferroptosis and improve treatment outcomes.展开更多
Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provide...Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.展开更多
TheαPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes se...TheαPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment,causing tumor immune evasion.Here,we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source,reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy.We developed sulfafurazole homodimers(SAS)with disulfide linkages,effectively releasing the drug in response to glutathione(GSH)and inhibiting 4T1 tumor-derived exosomes secretion.Subsequently,gemcitabine(Gem)was encapsulated to induce immunogenic cell death(ICD).Consequently,Gem@SAS inhibited the secretion of tumor exosomes by more than 70%,increased proliferation and granzyme B secretion ability of T cells by more than 2 times,and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.展开更多
Chemotherapy,as one of the most commonly used treatments for tumors,has been confirmed to induce immunogenic cell death(ICD)of tumor cells,which could activate a robust antitumor immune response.However,the elevated c...Chemotherapy,as one of the most commonly used treatments for tumors,has been confirmed to induce immunogenic cell death(ICD)of tumor cells,which could activate a robust antitumor immune response.However,the elevated cholesterol level in the tumor microenvironment(TME)promotes the activation and proliferation of myeloidderived suppressor cells(MDSCs),which would inhibit the antitumor effect,thereby reducing the therapeutic performance of chemo-immunotherapy.Here,a poly(lactide-coglycolide acid)(PLGA)-based nanotherapeutic platform(COD/MTO@PLGA@FA)is rationally designed by co-loading mitoxantrone(MTO)and cholesterol oxidase(COD)for boosting chemo-immunotherapy.Specifically,the designed COD/MTO@PLGA@FA would respond to the acidic TME to rapidly release MTO and COD,respectively.Thus,the free MTO could kill tumor cells directly and induce potent ICD,thereby activating the antitumor immune response.Meanwhile,the released COD could downregulate the expression of PD-1 on tumor-infiltrating CD8^(+)T cells by consuming cholesterol in TME,thereby reversing the exhausted state of tumor-infiltrating CD8^(+)T cells.Particularly,the reduction of cholesterol levels in TME would also inhibit the activation of MDSCs,further remodeling the immunosuppressive TME.In combination with anti-programmed death-ligand 1 antibody(αPD-L1),COD/MTO@PLGA@FA could significantly inhibit the growth of tumors,providing a practical strategy to enhance chemotherapy and highlighting new opportunities for chemo-immunotherapy.展开更多
Hypermutable cancers create opportunities for the development of various immunotherapies,such as immune checkpoint blockade(ICB)therapy.However,emergent studies have revealed that many hypermutated tumors have poor pr...Hypermutable cancers create opportunities for the development of various immunotherapies,such as immune checkpoint blockade(ICB)therapy.However,emergent studies have revealed that many hypermutated tumors have poor prognosis due to heterogeneous tumor antigen landscapes,yet the underlying mechanisms remain poorly understood.To understand the mechanisms that govern the responses to therapies,we develop mathematical models to explore the impact of combining chemotherapy and ICB therapy on heterogeneous tumors.Our results uncover how chemotherapy reduces antigenic heterogeneity,creating improved immunological conditions within tumors,which,in turn,enhances the therapeutic effect when combined with ICB.Furthermore,our results show that the recovery of the immune system after chemotherapy is crucial for enhancing the response to chemo-ICB combination therapy.展开更多
In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties ...In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel(NG@M) to co-deliver chemotherapeutic paclitaxel(PTX) and immunotherapeutic agent interleukin-2(IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate(39 days).展开更多
Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regim...Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regimen is chemotherapy combined with focused immunotherapy.This is implemented to induce the apoptosis of tumor cells and can activate immune responses,improving the clearance rate of primary lesions and maintaining the resistance to postoperative tumor recurrence and metastasis.Advances in micro/nanotechnology,nanomedicine and biomaterials have contributed to the development of enhanced local drug co-delivery systems for cancer treatment,improving tumor targeting and ameliorating severe systemic complications.Carrier materials can achieve the local long-term controllable release of multiple drugs,which not only avoids rapid drug diffusion from the pathological site,but can achieve synergistic effects at lower drug concentrations.Polymeric carriers display excellent biocompatibility and biodegradability;especially,some of them also have anti-tumor effects.The aim of this article was to review recent progress in the use of organic and polymeric materials for local tumor chemo-immunotherapy,which can be used as carriers for chemotherapeutic drugs,immune adjuvants and genes,including amphiphilic nanoparticles,nanocapsules,nano-disks,nano-polyplex particles,hydrogels and implantable materials.展开更多
Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling ...Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.展开更多
Combination therapy via nanoparticulate systems has already been proposed as a synergistic approach for cancer treatment. Herein, undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles （UnTH...Combination therapy via nanoparticulate systems has already been proposed as a synergistic approach for cancer treatment. Herein, undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles （UnTHCPSi NPs） loaded with sorafenib and surface-biofunctionalized with anti-CD326 antibody （Ab） were developed for cancer chemo-immunotherapy in MCF-7 and MDA-MB-231 breast cancer cells. The cytocompatibility study showed no significant toxicity for the bare and antibody-conjugated UnTHCPSi （Un-Ab） NPs at concentrations lower than 200 μg·mL^-1. Compared to the bare UnTHCPSi, Un-Ab NPs loaded with sorafenib reduced the premature drug release in plasma, increasing the probability of proper drug targeting. In addition, high cellular interaction and subsequent internalization of the Un-Ab NPs into the cells expressing CD326 antigen demonstrated the possibility of improving antigen-mediated endocytosis via CD326 targeting. While an in vitro antitumor study revealed a higher inhibitory effect of the sorafenib-loaded Un-Ab NPs compared to the drug-loaded UnTHCPSi NPs in the CD326 positive MCF-7 cells, there was no difference in the anti-proliferation impact of both the abovementioned NPs in the CD326 negative MDA-MB-231 cells, suggesting CD326 as an appropriate receptor for Ab-mediated drug delivery. It was also shown that the anti-CD326 Ab can act as an immunotherapeutic agent by inducing antibody dependent cellular cytotoxicity and enhancing the interaction of effector immune and cancer cells for subsequent phagocytosis and cytokine secretion. Hence, the developed nanovectors can be applied for simultaneous tumor-selective drug targeting and immunotherapy.展开更多
Herein,we designed Comp.1 to simultaneously respond to two enzymes:alkaline phosphatase and matrix metalloproteinase 2,which is commonly found in highly malignant cancer cell lines containing B16-F10 murine melanoma c...Herein,we designed Comp.1 to simultaneously respond to two enzymes:alkaline phosphatase and matrix metalloproteinase 2,which is commonly found in highly malignant cancer cell lines containing B16-F10 murine melanoma cells and CT26 murine colon carcinoma cells.We used the regional differences in the expression levels of dual-markers to accurately release immune molecule IND into tumor microenvironment for the activation of anti-tumor related immune effects,while in-situ self-assembly occurs.The dual-enzyme response process can further regulate the peptide precursors’self-assembly in the form of short rod-shaped nanofibers,enabling the delivery of the loaded chemotherapeutic drug HCPT into the cancer cells and further allowing the peptide assemblies to escape from lysosomes and return to cytoplasm in the form of tiny nanoparticles to induce apoptosis of cancer cells.This process does not occur in the single-positive breast cancer cell line MCF-7 or the normal hepatocytes cell line LO2,indicating the selectivity of the cancer cells exhibited using our strategy.In vivo studies revealed that Comp.1 can effectively cooperate with chemotherapy to enhance the immunotherapy effect and induce immune responses associated with elevated pro-inflammatory cytokines in vivo to inhibit malignant tumors growth.Our dual-enzyme responsive chemo-immunotherapy strategy feasible in anti-tumor treatment,provides a new avenue for regulating peptide self-assembly to adapt to diverse tumor properties and may eventually be used for the development of novel multifunctional anti-tumor nanomedicines.展开更多
Currently,the efficacy of albumin-bound paclitaxel(PTX@Alb)is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution.Meanwhile,acquired immune resistance alw...Currently,the efficacy of albumin-bound paclitaxel(PTX@Alb)is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution.Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1)expression after PTX@Alb treatment,which then leads to immune tolerance.To fill these gaps,we newly revealed that tamoxifen(TAM),a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity,could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK)protein.Following this,to obtain a more significant effect,TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine(TPP)with TAM,which then further self-assembledwith albumin(Alb)to form TPP-TAM@Alb nanoparticles.By doing this,TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro,which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors.Besides,TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration.All in all,we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors,further supporting its better clinical application。展开更多
A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer.However,the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location,and intrat...A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer.However,the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location,and intratumoral accumulation remains unsatisfactory.Here,an oral colon-specific drug delivery system(CBS-CS@Lipo/Oxp/MTZ)was constructed by covalently conjugating Clostridium butyricum spores(CBS)with drugs loaded chitosan(CS)-coated liposomes,where the model chemotherapy drug oxaliplatin(Oxp)and anti-anaerobic bacteria agent metronidazole(MTZ)were loaded.Following oral administration,CBS germinated into Clostridium butyricum(CB)and colonized in the colon.Combined with colonic specificallyβ-glucosidase responsive degrading of CS,dual colon-specific release of liposomes was achieved.And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold.Simultaneously,the released liposomes penetrated deep tumor tissue via the permeation enhancement effect of CS to kill localized intratumoral bacteria.Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB,the intratumoral pathogenic bacteria were eliminated fundamentally,blocking their recruitment to immunosuppressive cells.Furtherly,synchronized with lipopolysaccharide(LPS)released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells,they jointly enhanced tumor infiltration of CD8^(+)T cells and reactivated robust antitumor immunity.展开更多
Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously el...Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.展开更多
Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadva...Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapyenhanced immunotherapy. When arriving at the tumor site,the matrix metallopeptidase 2(MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and siteoriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues,recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.展开更多
Immune checkpoint blockade(ICB)has emerged as a promising immunotherapeutic modality against cancer in the clinic.However,only 10-30%of patients respond to ICB,primarily due to poor immunogenicity and insufficient T c...Immune checkpoint blockade(ICB)has emerged as a promising immunotherapeutic modality against cancer in the clinic.However,only 10-30%of patients respond to ICB,primarily due to poor immunogenicity and insufficient T cell infiltration in solid tumors.Herein,we presented an approach for high-performance cancer treatment using the programmed cell death protein-1 and programmed cell death ligand-1(PD-1/PD-L1)inhibitor(BMS-202)-loaded PEGylated graphene oxide(GPi).On the one hand,GPi dissociated tight junctions of vascular endothelial cells(VECs)in tumor,thus promoting the extravasation and intratumoral accumulation of liposomal doxorubicin(LipDox),which then effectively induced immunogenic cell death of tumor cells.On the other hand,GPi also stimulated VECs to upregulate the expression of cell-cell interaction molecules,such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1,which facilitated the infiltration of T cells in tumor.Beyond acting as a stimulator of VECs,GPi could exert responsive release of BMS-202 under the acidic tumor microenvironment and blockade PD-1/PD-L1 axis in tumors.Finally,the alternating administration of GPi and LipDox effectively inhibited tumor growth in a 4T1 tumor model,providing a novel treatment mode for chemo-immunotherapy.展开更多
基金supported by National Natural Science Foundation of China(No.82161138029)Liaoning Revitalization Talents Program(No.XLYC2402040)the Project of China-Japan Joint International Laboratory of Advanced Drug Delivery System Research and Translation of Liaoning Province(No.2024JH2/102100007).
文摘Local precise drug delivery is conducive to improving therapeutic efficacy and minimizing off-target toxicity.Current local delivery approaches are focused mostly on superficial or postoperative tumor lesions,due to the challenges posed by the inaccessibility of deep-seated tumors.Herein,we report a magnetic continuum soft robot capable of non-invasive and site-specific delivery of prodrug nanoassemblies-loaded hydrogel.The nanoassemblies are co-assembled from redox-responsive docetaxel prodrug and oxaliplatin prodrug,and subsequently embedded into a hydrogel matrix.The hydrogel precursor and crosslinker are synchronously delivered using the soft robot under magnetic guidance and in situ crosslinked at the gastric cancer lesions,forming a drug depot for sustained release and long-lasting treatment.As the hydrogel gradually degrades,the nanoassemblies are internalized by tumor cells.The redox response ability enables them to be selectively activatedwithin tumor cells to trigger the release of docetaxel and oxaliplatin,exerting a synergistic anti-tumor effect.We find that the combination effectively induces immunogenic cell death of gastric tumor,enhancing antitumor immune responses.This strategy offers an intelligent and controllable integration platform for precise drug delivery and combined chemo-immunotherapy.
基金partially supported by the National Natural Science Foundation of China(51802209,22077093,51761145041,51525203)the National Research Programs from Ministry of Science and Technology(MOST)of China(2016YFA0201200)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20180848)the Jiangsu Social Development Project(BE2019658)Collaborative Innovation Center of Suzhou Nano Science and Technologythe 111 Program from the Ministry of Education of China.
文摘Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.
基金supported by the Key R&D Program of Lishui City(2021ZDYF12,2022ZDYF07,2023zdyf14)Natural Science Foundation of China(82072026,82072025 and 82272090)+1 种基金Zhejiang Provincial Natural Science Foundation(LY23H180003,LQ22H180010)Provincial and Ministerial Joint Construction of Key Projects(WKJ-ZJ-2317).
文摘Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
基金The National Natural Science Foundation of China(Nos.82473864,82400095)the Natural Science Foundation of Jiangsu Province(No.BK20231009)+2 种基金the National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01015)“Double First-Class”Initiative Program in China Pharmaceutical Universitythe National Innovation and Entrepreneurship Training Program for Undergraduate(Nos.202310316007Z,2023103161133,2023103161333).
文摘Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.
基金financially supported by the National Natural Science Foundation of China(52373157 and 52003223)the Key Research and Development Program of Shaanxi Province(2024SF2-GJHX-26)the Guangdong Basic and Applied Basic Research Foundation(2024A1515010165)。
文摘Metastasis and heterogeneity pose major challenges in cancer treatment.Although chemoimmunotherapy shows promising efficacy,its therapeutic impact is limited by off-target effects and differences in the delivery sites of chemotherapeutic drugs and immunosuppressants.In this study,an engineered platelets(Pts)-based nano-aircraft,Pts@DOX/HANGs@Gal,was constructed with an internally loaded chemotherapeutic drug,doxorubicin,and externally grafted reduction-responsive hyaluronidase-cross-linked nanospheroids loaded with the immunosuppressant galunisertib for precise tumor chemo-immunotherapy.The normal physiological features of host Pts,including their excellent targeting capability for both metastatic and orthotopic tumors,are not disturbed by functional nanosystems.The interaction between Pts@DOX/HANGs@Gal and tumors gives rise to Pts activation,achieving the continuous targeted delivery of DOX to tumors,inducing the transition from cold to hot tumors,and promoting the recruitment of immune cells.Simultaneously,the external nanospheres disintegrate from Pts@DOX/HANGs@Gal,releasing galunisertib and hyaluronidase into the extracellular matrix to relieve immune tolerance and open up a high-speed channel for the tumor infiltration of immune cells and deep tumor penetration of the nanosystem.Consequently,Pts@DOX/HANGs@Gal not only effectively reinforced the antitumor immune response through self-recognized tumor-targeting chemo-immunotherapy and graded drug delivery but also reduced tumor metastasis in vivo.This study presents promising Pt-based nanovesicles for precise cancer treatment.
基金National Natural Science Foundation of China,Grant/Award Numbers:81874149,82171834,82303832,82403618China Postdoctoral Science Foundation,Grant/Award Number:2024M761039+5 种基金China National Postdoctoral Program for Innovative Talents,Grant/Award Number:BX20240129Postdoctor Project of Hubei Province,Grant/Award Number:2024HBBHCXA035Knowledge Innovation Program of Wuhan-ShuguangProject,Grant/Award Number:2022020801020456Key Research and Development Program of Social Development of Jiangsu Province,Grant/Award Number:BE2022725Suzhou Science and Technology Development Plan Project,Grant/Award Number:SKY2023049Jiangsu Province Seventh 333 High Level(Second Level)Talents Project。
文摘Background:Intrahepatic cholangiocarcinoma(ICC)is a challenging can-cer with an increasing incidence.The Phase III TOPAZ-1/KEYNOTE-966study demonstrated chemo-immunotherapy(CIT)as a significant advance-ment,potentially replacing traditional chemotherapy for advanced biliary tractcancer.Ferroptosis is a crucial process that affects cancer cell survival andtherapy resistance.Although AKT hyperactivation is prevalent in numerouscancers,including ICC,its role in ferroptosis resistance remains unclear.Thisstudy explored whether targeting ferroptosis can enhance CIT response rates,specifically in ICC patients with AKT hyperactivation.Methods:In vivo metabolic CRISPR screening in a KrasG12D/Tp53−/−ICCmouse model was used to identify primary regulators of ferroptosis duringCIT(gemcitabine,cisplatin,and anti-mouse programmed cell death 1 ligand 1).Phosphoenolpyruvate carboxykinase 1(PCK1)was assessed for its role in fer-roptosis and treatment resistance in preclinical models under AKT activationlevels.Molecular and biochemical techniques were used to explore PCK1-relatedresistance mechanisms in AKT-hyperactivated ICC.Results:Under AKT hyperactivation condition,phosphorylated PCK1(pPCK1)promoted metabolic reprogramming,enhancing ubiquinol and menaquinone-4synthesisthrough the mevalonate(MVA)pathway.This cascade was mediated bythe pPCK1-pLDHA-SPRINGlac axis.Inhibiting PCK1 phosphorylation or usingsimvastatin significantly augmented CIT efficacy in preclinical models.Clini-cal data further indicated that phosphorylated AKT(pAKT)-pPCK1 levels mightserve as a biomarker to predict CIT response in ICC.Conclusion:Thisstudy identified the pAKT-pPCK1-pLDHA-SPRINGlac axis asa novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC byassociating glycolytic activation with MVA flux reprogramming.Targeting thisaxis,potentially through statin-based therapies,may offer a strategy to sensitizeICC cells to ferroptosis and improve treatment outcomes.
基金supported by the Natural Science Foundation of Shandong province(ZR2023QH204 and ZR2024ME024,China).
文摘Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.
基金supported by the National Natural Science Foundation of China(82473866 and 32471394)Key Research and Development Program Social Development Project of Jiangsu Province(BE2023845,China)Natural Science Foundation of Jiangsu Province(BK20210424,China).
文摘TheαPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment,causing tumor immune evasion.Here,we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source,reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy.We developed sulfafurazole homodimers(SAS)with disulfide linkages,effectively releasing the drug in response to glutathione(GSH)and inhibiting 4T1 tumor-derived exosomes secretion.Subsequently,gemcitabine(Gem)was encapsulated to induce immunogenic cell death(ICD).Consequently,Gem@SAS inhibited the secretion of tumor exosomes by more than 70%,increased proliferation and granzyme B secretion ability of T cells by more than 2 times,and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.
基金supported by the National Natural Science Foundation of China(52473145,52333004,52273301,and 22135005)the National Key Research and Development Program of China(2022YFB3804600)。
文摘Chemotherapy,as one of the most commonly used treatments for tumors,has been confirmed to induce immunogenic cell death(ICD)of tumor cells,which could activate a robust antitumor immune response.However,the elevated cholesterol level in the tumor microenvironment(TME)promotes the activation and proliferation of myeloidderived suppressor cells(MDSCs),which would inhibit the antitumor effect,thereby reducing the therapeutic performance of chemo-immunotherapy.Here,a poly(lactide-coglycolide acid)(PLGA)-based nanotherapeutic platform(COD/MTO@PLGA@FA)is rationally designed by co-loading mitoxantrone(MTO)and cholesterol oxidase(COD)for boosting chemo-immunotherapy.Specifically,the designed COD/MTO@PLGA@FA would respond to the acidic TME to rapidly release MTO and COD,respectively.Thus,the free MTO could kill tumor cells directly and induce potent ICD,thereby activating the antitumor immune response.Meanwhile,the released COD could downregulate the expression of PD-1 on tumor-infiltrating CD8^(+)T cells by consuming cholesterol in TME,thereby reversing the exhausted state of tumor-infiltrating CD8^(+)T cells.Particularly,the reduction of cholesterol levels in TME would also inhibit the activation of MDSCs,further remodeling the immunosuppressive TME.In combination with anti-programmed death-ligand 1 antibody(αPD-L1),COD/MTO@PLGA@FA could significantly inhibit the growth of tumors,providing a practical strategy to enhance chemotherapy and highlighting new opportunities for chemo-immunotherapy.
基金Xiamen University overseas study program for graduate studentsNational Natural Science Foundation of China,Grant/Award Numbers:11971405,12471475,32270693,82241236+1 种基金Basic and Applied Basic Research Foundation of Guangdong Province,Grant/Award Number:2021B1515020042Central University Basic Research Fund of China,Grant/Award Numbers:20720240151,20720230023。
文摘Hypermutable cancers create opportunities for the development of various immunotherapies,such as immune checkpoint blockade(ICB)therapy.However,emergent studies have revealed that many hypermutated tumors have poor prognosis due to heterogeneous tumor antigen landscapes,yet the underlying mechanisms remain poorly understood.To understand the mechanisms that govern the responses to therapies,we develop mathematical models to explore the impact of combining chemotherapy and ICB therapy on heterogeneous tumors.Our results uncover how chemotherapy reduces antigenic heterogeneity,creating improved immunological conditions within tumors,which,in turn,enhances the therapeutic effect when combined with ICB.Furthermore,our results show that the recovery of the immune system after chemotherapy is crucial for enhancing the response to chemo-ICB combination therapy.
基金supported by National Natural Science Foundation of China (81673374,China)Program for HUST Academic Frontier Youth Team (2018QYTD13,China)Natural Science Foundation of Hubei Province (2020CFB301,China)。
文摘In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel(NG@M) to co-deliver chemotherapeutic paclitaxel(PTX) and immunotherapeutic agent interleukin-2(IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate(39 days).
基金supported by the National Natural Science Foundation of China(Grant Nos.51973218,51833010,51622307)the Youth Innovation Promotion Association of the Chinese Academy of Sciences。
文摘Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regimen is chemotherapy combined with focused immunotherapy.This is implemented to induce the apoptosis of tumor cells and can activate immune responses,improving the clearance rate of primary lesions and maintaining the resistance to postoperative tumor recurrence and metastasis.Advances in micro/nanotechnology,nanomedicine and biomaterials have contributed to the development of enhanced local drug co-delivery systems for cancer treatment,improving tumor targeting and ameliorating severe systemic complications.Carrier materials can achieve the local long-term controllable release of multiple drugs,which not only avoids rapid drug diffusion from the pathological site,but can achieve synergistic effects at lower drug concentrations.Polymeric carriers display excellent biocompatibility and biodegradability;especially,some of them also have anti-tumor effects.The aim of this article was to review recent progress in the use of organic and polymeric materials for local tumor chemo-immunotherapy,which can be used as carriers for chemotherapeutic drugs,immune adjuvants and genes,including amphiphilic nanoparticles,nanocapsules,nano-disks,nano-polyplex particles,hydrogels and implantable materials.
基金This work was supported by the National Natural Science Foundation of China(82173682,China)Shenzhen Science and Technology Program(JCYJ20210324133213037,China)Innovation Capability Support Program of Shaanxi(2021KJXX-92,China)。
文摘Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.
文摘Combination therapy via nanoparticulate systems has already been proposed as a synergistic approach for cancer treatment. Herein, undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles （UnTHCPSi NPs） loaded with sorafenib and surface-biofunctionalized with anti-CD326 antibody （Ab） were developed for cancer chemo-immunotherapy in MCF-7 and MDA-MB-231 breast cancer cells. The cytocompatibility study showed no significant toxicity for the bare and antibody-conjugated UnTHCPSi （Un-Ab） NPs at concentrations lower than 200 μg·mL^-1. Compared to the bare UnTHCPSi, Un-Ab NPs loaded with sorafenib reduced the premature drug release in plasma, increasing the probability of proper drug targeting. In addition, high cellular interaction and subsequent internalization of the Un-Ab NPs into the cells expressing CD326 antigen demonstrated the possibility of improving antigen-mediated endocytosis via CD326 targeting. While an in vitro antitumor study revealed a higher inhibitory effect of the sorafenib-loaded Un-Ab NPs compared to the drug-loaded UnTHCPSi NPs in the CD326 positive MCF-7 cells, there was no difference in the anti-proliferation impact of both the abovementioned NPs in the CD326 negative MDA-MB-231 cells, suggesting CD326 as an appropriate receptor for Ab-mediated drug delivery. It was also shown that the anti-CD326 Ab can act as an immunotherapeutic agent by inducing antibody dependent cellular cytotoxicity and enhancing the interaction of effector immune and cancer cells for subsequent phagocytosis and cytokine secretion. Hence, the developed nanovectors can be applied for simultaneous tumor-selective drug targeting and immunotherapy.
基金supported by the National Key Research and Development Program of China(2022YFB3804600)the National Natural Science Foundation of China(32171325,32301122 and 82261160656).
文摘Herein,we designed Comp.1 to simultaneously respond to two enzymes:alkaline phosphatase and matrix metalloproteinase 2,which is commonly found in highly malignant cancer cell lines containing B16-F10 murine melanoma cells and CT26 murine colon carcinoma cells.We used the regional differences in the expression levels of dual-markers to accurately release immune molecule IND into tumor microenvironment for the activation of anti-tumor related immune effects,while in-situ self-assembly occurs.The dual-enzyme response process can further regulate the peptide precursors’self-assembly in the form of short rod-shaped nanofibers,enabling the delivery of the loaded chemotherapeutic drug HCPT into the cancer cells and further allowing the peptide assemblies to escape from lysosomes and return to cytoplasm in the form of tiny nanoparticles to induce apoptosis of cancer cells.This process does not occur in the single-positive breast cancer cell line MCF-7 or the normal hepatocytes cell line LO2,indicating the selectivity of the cancer cells exhibited using our strategy.In vivo studies revealed that Comp.1 can effectively cooperate with chemotherapy to enhance the immunotherapy effect and induce immune responses associated with elevated pro-inflammatory cytokines in vivo to inhibit malignant tumors growth.Our dual-enzyme responsive chemo-immunotherapy strategy feasible in anti-tumor treatment,provides a new avenue for regulating peptide self-assembly to adapt to diverse tumor properties and may eventually be used for the development of novel multifunctional anti-tumor nanomedicines.
基金the National Natural Science Foundation of China(22377093)the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR23C100001,China)the Zhejiang Qianjiang Talent Plan(QJD20020224,China).
文摘Currently,the efficacy of albumin-bound paclitaxel(PTX@Alb)is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution.Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1)expression after PTX@Alb treatment,which then leads to immune tolerance.To fill these gaps,we newly revealed that tamoxifen(TAM),a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity,could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK)protein.Following this,to obtain a more significant effect,TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine(TPP)with TAM,which then further self-assembledwith albumin(Alb)to form TPP-TAM@Alb nanoparticles.By doing this,TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro,which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors.Besides,TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration.All in all,we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors,further supporting its better clinical application。
基金National Natural Science Foundation of China(Nos.82171333,82272847,82202318)Postdoctoral Fellowship Program of CPSF(GZB20230675,China)+2 种基金The Henan Province Fund for Cultivating Advantageous Disciplines(No.222301420012,China)Central Plains Science and Technology Innovation Leading Talent Project(No.234200510005,China)Graduate Education Reform Project of Henan Province(2023SJGLX127Y,China).
文摘A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer.However,the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location,and intratumoral accumulation remains unsatisfactory.Here,an oral colon-specific drug delivery system(CBS-CS@Lipo/Oxp/MTZ)was constructed by covalently conjugating Clostridium butyricum spores(CBS)with drugs loaded chitosan(CS)-coated liposomes,where the model chemotherapy drug oxaliplatin(Oxp)and anti-anaerobic bacteria agent metronidazole(MTZ)were loaded.Following oral administration,CBS germinated into Clostridium butyricum(CB)and colonized in the colon.Combined with colonic specificallyβ-glucosidase responsive degrading of CS,dual colon-specific release of liposomes was achieved.And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold.Simultaneously,the released liposomes penetrated deep tumor tissue via the permeation enhancement effect of CS to kill localized intratumoral bacteria.Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB,the intratumoral pathogenic bacteria were eliminated fundamentally,blocking their recruitment to immunosuppressive cells.Furtherly,synchronized with lipopolysaccharide(LPS)released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells,they jointly enhanced tumor infiltration of CD8^(+)T cells and reactivated robust antitumor immunity.
基金supported by grants from the National Natural Science Foundation of China(Nos.32000998,and 32201240)The Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2022HYTP046)+2 种基金the China Postdoctoral Science Foundation(Nos.2019TQ0285,2019M662513,and 2021TQ0298)Henan provincial Medical Science and Technology Research Project(No.LHGJ20210210)Science and Technology Development Project of Henan Province(Nos.212102310138 and 222102310525).
文摘Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.
基金supported by the National Natural Science Foundation of China (21874078 and 22074072)Taishan Young Scholar Program of Shandong Province (tsqn20161027)+2 种基金the Natural Science Foundation of Shandong Province (ZR2019BH032)the People’s Livelihood Science and Technology Project of Qingdao (166257nsh and 173378nsh)the First-Class Discipline Project of Shandong Province。
文摘Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapyenhanced immunotherapy. When arriving at the tumor site,the matrix metallopeptidase 2(MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and siteoriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues,recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.
文摘Immune checkpoint blockade(ICB)has emerged as a promising immunotherapeutic modality against cancer in the clinic.However,only 10-30%of patients respond to ICB,primarily due to poor immunogenicity and insufficient T cell infiltration in solid tumors.Herein,we presented an approach for high-performance cancer treatment using the programmed cell death protein-1 and programmed cell death ligand-1(PD-1/PD-L1)inhibitor(BMS-202)-loaded PEGylated graphene oxide(GPi).On the one hand,GPi dissociated tight junctions of vascular endothelial cells(VECs)in tumor,thus promoting the extravasation and intratumoral accumulation of liposomal doxorubicin(LipDox),which then effectively induced immunogenic cell death of tumor cells.On the other hand,GPi also stimulated VECs to upregulate the expression of cell-cell interaction molecules,such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1,which facilitated the infiltration of T cells in tumor.Beyond acting as a stimulator of VECs,GPi could exert responsive release of BMS-202 under the acidic tumor microenvironment and blockade PD-1/PD-L1 axis in tumors.Finally,the alternating administration of GPi and LipDox effectively inhibited tumor growth in a 4T1 tumor model,providing a novel treatment mode for chemo-immunotherapy.
