Although with aggressive standards of care like surgical resection,chemotherapy,and radiation,high-grade gliomas(HGGs)and brain metastases(BM)treatment has remained challenging for more than two decades.However,techno...Although with aggressive standards of care like surgical resection,chemotherapy,and radiation,high-grade gliomas(HGGs)and brain metastases(BM)treatment has remained challenging for more than two decades.However,technological advances in this field and immunotherapeutic strategies have revolutionized the treatment of HGGs and BM.Immunotherapies like immune checkpoint inhibitors,CAR-T targeting,oncolytic virus-based therapy,bispecific antibody treatment,and vaccination approaches,etc.,are emerging as promising avenues offering new hope in refining patient’s survival benefits.However,selective trafficking across the blood-brain barrier(BBB),immunosuppressive tumor microenvironment(TME),metabolic alteration,and tumor heterogeneity limit the therapeutic efficacy of immunotherapy for HGGs and BM.Furthermore,to address this concern,the NanoBioTechnology-based bioinspired delivery system has been gaining tremendous attention in recent years.With technological advances such as Trojan horse targeting and infusing/camouflaging nanoparticles surface with biological molecules/cells like immunocytes,erythrocytes,platelets,glioma cell lysate and/or integrating these strategies to get hybrid membrane for homotypic recognition.These biomimetic nanotherapy offers advantages over conventional nanoparticles,focusing on greater target specificity,increased circulation stability,higher active loading capacity,BBB permeability(inherent inflammatory chemotaxis of neutrophils),decreased immunogenicity,efficient metabolism-based combinatorial effects,and prevention of tumor recurrence by induction of immunological memory,etc.provide new age of improved immunotherapies outcomes against HGGs and BM.In this review,we emphasize on neuro-immunotherapy and the versatility of these biomimetic nano-delivery strategies for precise targeting of hard-to-treat andmost lethal HGGs and BM.Moreover,the challenges impeding the clinical translatability of these approaches were addressed to unmet medical needs of brain cancers.展开更多
Nanoparticles(NPs)play dual roles in neurodegeneration.Incidental NPs,generated unintentionally from environmental and industrial sources,are linked to oxidative stress,neuroinflammation,and disruption of the blood-br...Nanoparticles(NPs)play dual roles in neurodegeneration.Incidental NPs,generated unintentionally from environmental and industrial sources,are linked to oxidative stress,neuroinflammation,and disruption of the blood-brain barrier in Alzheimer’s disease(AD)and Parkinson’s disease(PD).Engineered NPs are designed for diagnosis and therapy using nanobodies,nanozymes,and other engineered nanoparticle(ENP)platforms that enable targeted delivery,modulation of neuroimmune pathways,and interference with pathological protein aggregation.This review aligns source-based classes(incidental versus engineered)with composition-based families(metal-based,carbon-based,and polymeric or inorganic),and summarizes routes of exposure,mechanistic toxicology,and engineered interventions relevant to AD and PD.We also evaluate current limitations,including biocompatibility,relevance to chronic exposure,and clinical benchmarking,and we outline priorities for translating nanotechnology into practical diagnostics and therapeutics for neurodegenerative disease.展开更多
Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studyin...Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone.To visualize calvarial 3D neurovascular architecture,we imaged nerves and endothelial cells with lightsheet microscopy.展开更多
Peripheral nerve injuries remain a challenging problem in need of better treatment strategies.Despite best efforts at surgical reconstruction and postoperative rehabilitation,patients are often left with persistent,de...Peripheral nerve injuries remain a challenging problem in need of better treatment strategies.Despite best efforts at surgical reconstruction and postoperative rehabilitation,patients are often left with persistent,debilitating motor and sensory deficits.There are currently no therapeutic strategies proven to enhance the regenerative process in humans.A clinical need exists for the development of technologies to promote nerve regeneration and improve functional outcomes.Recent advances in the fields of tissue engineering and nanotechnology have enabled biomaterial scaffolds to modulate the host response to tissue repair through tailored mechanical,chemical,and conductive cues.New bioengineered approaches have enabled targeted,sustained delivery of protein therapeutics with the capacity to unlock the clinical potential of a myriad of neurotrophic growth factors that have demonstrated promise in enhancing regenerative outcomes.As such,further exploration of combinatory strategies leveraging these technological advances may offer a pathway towards clinically translatable solutions to advance the care of patients with peripheral nerve injuries.This review first presents the various emerging bioengineering strategies that can be applied for the management of nerve gap injuries.We cover the rationale and limitations for their use as an alternative to autografts,focusing on the approaches to increase the number of regenerating axons crossing the repair site,and facilitating their growth towards the distal stump.We also discuss the emerging growth factor-based therapeutic strategies designed to improve functional outcomes in a multimodal fashion,by accelerating axonal growth,improving the distal regenerative environment,and preventing end-organs atrophy.展开更多
The applications of supramolecular metal-peptide assemblies as catalyst or catalyst precursor have recent attracted increasing attentions.In this work,a fragment of the amyloid β-peptide,NH_(2)-KLVFF-COOH,was assembl...The applications of supramolecular metal-peptide assemblies as catalyst or catalyst precursor have recent attracted increasing attentions.In this work,a fragment of the amyloid β-peptide,NH_(2)-KLVFF-COOH,was assembled into nanofilms with encapsulated Pd,Pt and Au nanoparticles(NPs)via a one-step room temperature electron induction method.The effects of building block,intermolecular interaction,driving force and side-chain on the assembly were investigated.The assembly mechanism was thereby proposed.The crosslinking of peptide monomers results in mainly random and unordered structures.The obtained metal-peptide assemblies are extremely stable in water at neutral pH for long term.However,the metal NPs are able to be responsively released under basic and reductive conditions.The released NPs show a high activity to catalyze the reduction of 4-nitrophenol.The present studies on assembly mechanism and responsive release will be helpful for the design of organic skeletons and also for the future development of peptide stabilized metallic NPs with applications beyond catalysts.展开更多
Calcium ion-crosslinked alginate hydrogels are widely used as a materials system for investigating cell behavior in 3D environments in vitro.Suspensions of calcium sulfate particles are often used as the source of Ca2...Calcium ion-crosslinked alginate hydrogels are widely used as a materials system for investigating cell behavior in 3D environments in vitro.Suspensions of calcium sulfate particles are often used as the source of Ca2+to control the rate of gelation.However,the instability of calcium sulfate suspensions can increase chances of reduced homogeneity of the resulting gel and requires researcher’s proficiency.Here,we show that ball-milled calcium sulfate microparticles(MPs)with smaller sizes can create more stable crosslinker suspensions than unprocessed or simply autoclaved calcium sulfate particles.In particular,15μm ball-milled calcium sulfate MPs result in gels that are more homogeneous with a balanced gelation rate,which facilitates fabrication of gels with consistent mechanical properties and reliable performance for 3D cell culture.Overall,these MPs represent an improved method for alginate hydrogel fabrication that can increase experimental reliability and quality for 3D cell culture.展开更多
Lymph node (LN) targeti ng through interstitial drain age of nan oparticles (NPs) is an attractive strategy to stimulate a pote nt immune respo nse, as LNs are the primary site for lymphocyte priming by antigen presen...Lymph node (LN) targeti ng through interstitial drain age of nan oparticles (NPs) is an attractive strategy to stimulate a pote nt immune respo nse, as LNs are the primary site for lymphocyte priming by antigen presenting cells (APCs) and triggering of an adaptive immune response. NP size has been shown to influence the efficiency of LN-targeting and retention after subcutaneous injection. For clinical translation, biodegradable NPs are preferred as carrier for vaccine delivery. However, the selective "size gateM for effective LN-drainage, particularly the kinetics of LN trafficking, is less well defined. This is partly due to the challenge in generating size-controlled NPs from biodegradable polymers in the sub-100-nm range. Here, we report the preparation of three sets of poly(lactic-co-glycolic)-b-poly(ethylene-glycol)(PLGA-b-PEG) NPs with number average diameters of 20-, 40-, and 100-nm and narrow size distributions using flash nanoprecipitation. Using NPs labeled with a near-infrared dye, we showed that 20-nm NPs drain rapidly across proximal and distal LNs following subcutaneous inoculation in mice and are retai ned in LNs more effectively than NPs with a nu mber average diameter of 40-nm. The drain age of 100-nm NPs was n egligible. Furthermore, the 20-nm NPs showed the highest degree of penetration around the paracortex region and had enhanced access to dendritic cells in the LNs. Together, these data confirmed that small, size-controlled PLGA-b-PEG NPs at the lower threshold of about 30-nm are most effective for LN trafficking, retention, and APC uptake after s.c. administration. This report could inform the design of LN-targeted NP carrier for the delivery of therapeutic or prophylactic vaccines.展开更多
Adoptive cell therapy(ACT)is an immunotherapy strategy for cancer that has seen widespread clinical success.During ACT,patient-derived lymphocytes are stimulated with the antigen of interest ex vivo,proliferated,then ...Adoptive cell therapy(ACT)is an immunotherapy strategy for cancer that has seen widespread clinical success.During ACT,patient-derived lymphocytes are stimulated with the antigen of interest ex vivo,proliferated,then returned to the patient to initiate an antigen-specific antitumor response.While effective,this process is resource-intensive and logistically impossible for many patients.Particulate artificial antigen presenting cells(aAPCs)offer a potential“off-the-shelf”alternative to ex vivo ACT.While particulate aAPCs perform well in vitro,they have had limited success in vivo due to poor bioavailability after injection.Barriers to bioavailability include rapid clearance,unfavorable biodistribution,and inadequate interactions with CD8+T cells at sites of interest.Biomaterial properties such as elasticity have been shown to vastly impact the bioavailability and particle-cell interactions,but this has yet to be investigated in the context of aAPCs for in vivo T-cell stimulation.Previous literature likewise indicates that biomaterial properties,especially elasticity,can modulate T-cell activation in vitro.With the goal of creating a more biomimetic,next-generation particulate aAPC,we developed a poly(ethylene)glycol hydrogel particle platform with tunable elasticity to investigate the impact of elasticity on antigen-specific T cell activation for in vivo adoptive transfer.Using this knowledge,we were able to gain more precise control over in vivo T cell activation and investigate possible mechanisms including the effects of aAPC elasticity on T cell binding,macrophage uptake,and the protein corona.展开更多
DNA methylation is a reversible process catalyzed by the ten-eleven translocation(TET)family of enzymes(TET1,TET2,TET3)that convert 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).Altered patterns of 5hmC and 5m...DNA methylation is a reversible process catalyzed by the ten-eleven translocation(TET)family of enzymes(TET1,TET2,TET3)that convert 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis.展开更多
文摘Although with aggressive standards of care like surgical resection,chemotherapy,and radiation,high-grade gliomas(HGGs)and brain metastases(BM)treatment has remained challenging for more than two decades.However,technological advances in this field and immunotherapeutic strategies have revolutionized the treatment of HGGs and BM.Immunotherapies like immune checkpoint inhibitors,CAR-T targeting,oncolytic virus-based therapy,bispecific antibody treatment,and vaccination approaches,etc.,are emerging as promising avenues offering new hope in refining patient’s survival benefits.However,selective trafficking across the blood-brain barrier(BBB),immunosuppressive tumor microenvironment(TME),metabolic alteration,and tumor heterogeneity limit the therapeutic efficacy of immunotherapy for HGGs and BM.Furthermore,to address this concern,the NanoBioTechnology-based bioinspired delivery system has been gaining tremendous attention in recent years.With technological advances such as Trojan horse targeting and infusing/camouflaging nanoparticles surface with biological molecules/cells like immunocytes,erythrocytes,platelets,glioma cell lysate and/or integrating these strategies to get hybrid membrane for homotypic recognition.These biomimetic nanotherapy offers advantages over conventional nanoparticles,focusing on greater target specificity,increased circulation stability,higher active loading capacity,BBB permeability(inherent inflammatory chemotaxis of neutrophils),decreased immunogenicity,efficient metabolism-based combinatorial effects,and prevention of tumor recurrence by induction of immunological memory,etc.provide new age of improved immunotherapies outcomes against HGGs and BM.In this review,we emphasize on neuro-immunotherapy and the versatility of these biomimetic nano-delivery strategies for precise targeting of hard-to-treat andmost lethal HGGs and BM.Moreover,the challenges impeding the clinical translatability of these approaches were addressed to unmet medical needs of brain cancers.
基金the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Program M-2023.This work was supported by the NIH AG079487(X.B.M.)the Adrienne Helis Malvin Medical Research Foundation(X.B.M.)+2 种基金the Parkinson’s Foundation(No.PF-JFA-1933)the Maryland Stem Cell Research Foundation(Nos.2019-MSCRFD-4292 and 2024-MSCRFD-6394)the American Parkinson’s Disease Association(X.B.M.).
文摘Nanoparticles(NPs)play dual roles in neurodegeneration.Incidental NPs,generated unintentionally from environmental and industrial sources,are linked to oxidative stress,neuroinflammation,and disruption of the blood-brain barrier in Alzheimer’s disease(AD)and Parkinson’s disease(PD).Engineered NPs are designed for diagnosis and therapy using nanobodies,nanozymes,and other engineered nanoparticle(ENP)platforms that enable targeted delivery,modulation of neuroimmune pathways,and interference with pathological protein aggregation.This review aligns source-based classes(incidental versus engineered)with composition-based families(metal-based,carbon-based,and polymeric or inorganic),and summarizes routes of exposure,mechanistic toxicology,and engineered interventions relevant to AD and PD.We also evaluate current limitations,including biocompatibility,relevance to chronic exposure,and clinical benchmarking,and we outline priorities for translating nanotechnology into practical diagnostics and therapeutics for neurodegenerative disease.
基金supported by funding from NIDCR(1R01DE027957)Maryland Stem Cell Research Fund(2022-MSCRFV-5782)the NSF GRFP and NCI(5R01CA237597-05,2R01CA196701-06A1).
文摘Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone.To visualize calvarial 3D neurovascular architecture,we imaged nerves and endothelial cells with lightsheet microscopy.
基金supported by The Plastic Surgery Foundation Research Pilot Grant,No.627383(to KAS).
文摘Peripheral nerve injuries remain a challenging problem in need of better treatment strategies.Despite best efforts at surgical reconstruction and postoperative rehabilitation,patients are often left with persistent,debilitating motor and sensory deficits.There are currently no therapeutic strategies proven to enhance the regenerative process in humans.A clinical need exists for the development of technologies to promote nerve regeneration and improve functional outcomes.Recent advances in the fields of tissue engineering and nanotechnology have enabled biomaterial scaffolds to modulate the host response to tissue repair through tailored mechanical,chemical,and conductive cues.New bioengineered approaches have enabled targeted,sustained delivery of protein therapeutics with the capacity to unlock the clinical potential of a myriad of neurotrophic growth factors that have demonstrated promise in enhancing regenerative outcomes.As such,further exploration of combinatory strategies leveraging these technological advances may offer a pathway towards clinically translatable solutions to advance the care of patients with peripheral nerve injuries.This review first presents the various emerging bioengineering strategies that can be applied for the management of nerve gap injuries.We cover the rationale and limitations for their use as an alternative to autografts,focusing on the approaches to increase the number of regenerating axons crossing the repair site,and facilitating their growth towards the distal stump.We also discuss the emerging growth factor-based therapeutic strategies designed to improve functional outcomes in a multimodal fashion,by accelerating axonal growth,improving the distal regenerative environment,and preventing end-organs atrophy.
文摘The applications of supramolecular metal-peptide assemblies as catalyst or catalyst precursor have recent attracted increasing attentions.In this work,a fragment of the amyloid β-peptide,NH_(2)-KLVFF-COOH,was assembled into nanofilms with encapsulated Pd,Pt and Au nanoparticles(NPs)via a one-step room temperature electron induction method.The effects of building block,intermolecular interaction,driving force and side-chain on the assembly were investigated.The assembly mechanism was thereby proposed.The crosslinking of peptide monomers results in mainly random and unordered structures.The obtained metal-peptide assemblies are extremely stable in water at neutral pH for long term.However,the metal NPs are able to be responsively released under basic and reductive conditions.The released NPs show a high activity to catalyze the reduction of 4-nitrophenol.The present studies on assembly mechanism and responsive release will be helpful for the design of organic skeletons and also for the future development of peptide stabilized metallic NPs with applications beyond catalysts.
基金supported by the National Institute on Aging of the National Institutes of Health under Award Number R03AG073834the National Heart,Lung,and Blood Institute of the National Institutes of Health under Award Number R56HL169764+1 种基金the Air Force Office of Scientific Research award FA9550-24-1-0286the Maryland Stem Cell Research Fund 2024-MSCRFL-6272.
文摘Calcium ion-crosslinked alginate hydrogels are widely used as a materials system for investigating cell behavior in 3D environments in vitro.Suspensions of calcium sulfate particles are often used as the source of Ca2+to control the rate of gelation.However,the instability of calcium sulfate suspensions can increase chances of reduced homogeneity of the resulting gel and requires researcher’s proficiency.Here,we show that ball-milled calcium sulfate microparticles(MPs)with smaller sizes can create more stable crosslinker suspensions than unprocessed or simply autoclaved calcium sulfate particles.In particular,15μm ball-milled calcium sulfate MPs result in gels that are more homogeneous with a balanced gelation rate,which facilitates fabrication of gels with consistent mechanical properties and reliable performance for 3D cell culture.Overall,these MPs represent an improved method for alginate hydrogel fabrication that can increase experimental reliability and quality for 3D cell culture.
文摘Lymph node (LN) targeti ng through interstitial drain age of nan oparticles (NPs) is an attractive strategy to stimulate a pote nt immune respo nse, as LNs are the primary site for lymphocyte priming by antigen presenting cells (APCs) and triggering of an adaptive immune response. NP size has been shown to influence the efficiency of LN-targeting and retention after subcutaneous injection. For clinical translation, biodegradable NPs are preferred as carrier for vaccine delivery. However, the selective "size gateM for effective LN-drainage, particularly the kinetics of LN trafficking, is less well defined. This is partly due to the challenge in generating size-controlled NPs from biodegradable polymers in the sub-100-nm range. Here, we report the preparation of three sets of poly(lactic-co-glycolic)-b-poly(ethylene-glycol)(PLGA-b-PEG) NPs with number average diameters of 20-, 40-, and 100-nm and narrow size distributions using flash nanoprecipitation. Using NPs labeled with a near-infrared dye, we showed that 20-nm NPs drain rapidly across proximal and distal LNs following subcutaneous inoculation in mice and are retai ned in LNs more effectively than NPs with a nu mber average diameter of 40-nm. The drain age of 100-nm NPs was n egligible. Furthermore, the 20-nm NPs showed the highest degree of penetration around the paracortex region and had enhanced access to dendritic cells in the LNs. Together, these data confirmed that small, size-controlled PLGA-b-PEG NPs at the lower threshold of about 30-nm are most effective for LN trafficking, retention, and APC uptake after s.c. administration. This report could inform the design of LN-targeted NP carrier for the delivery of therapeutic or prophylactic vaccines.
基金the NIH for support of this research(P41EB028239)the National Science Foundation Graduate Research Fellowship(Nos.DGE-1746891(SEW)and DGE-1746891(SRS)).
文摘Adoptive cell therapy(ACT)is an immunotherapy strategy for cancer that has seen widespread clinical success.During ACT,patient-derived lymphocytes are stimulated with the antigen of interest ex vivo,proliferated,then returned to the patient to initiate an antigen-specific antitumor response.While effective,this process is resource-intensive and logistically impossible for many patients.Particulate artificial antigen presenting cells(aAPCs)offer a potential“off-the-shelf”alternative to ex vivo ACT.While particulate aAPCs perform well in vitro,they have had limited success in vivo due to poor bioavailability after injection.Barriers to bioavailability include rapid clearance,unfavorable biodistribution,and inadequate interactions with CD8+T cells at sites of interest.Biomaterial properties such as elasticity have been shown to vastly impact the bioavailability and particle-cell interactions,but this has yet to be investigated in the context of aAPCs for in vivo T-cell stimulation.Previous literature likewise indicates that biomaterial properties,especially elasticity,can modulate T-cell activation in vitro.With the goal of creating a more biomimetic,next-generation particulate aAPC,we developed a poly(ethylene)glycol hydrogel particle platform with tunable elasticity to investigate the impact of elasticity on antigen-specific T cell activation for in vivo adoptive transfer.Using this knowledge,we were able to gain more precise control over in vivo T cell activation and investigate possible mechanisms including the effects of aAPC elasticity on T cell binding,macrophage uptake,and the protein corona.
文摘DNA methylation is a reversible process catalyzed by the ten-eleven translocation(TET)family of enzymes(TET1,TET2,TET3)that convert 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis.
