Photodynamic therapy(PDT)induces tumor cell pyroptosis,a form of programmed cell death that triggers antitumor immunity.However,high glucose metabolism and hypoxic conditions in the tumor microenvironment(TME)limit PD...Photodynamic therapy(PDT)induces tumor cell pyroptosis,a form of programmed cell death that triggers antitumor immunity.However,high glucose metabolism and hypoxic conditions in the tumor microenvironment(TME)limit PDT efficiency and impair effector cell function.Here,we propose a cancer metabolic reprogramming-enabling photoresponsive nanoproteolysis-targeting chimera(Nano-PROTAC;NanoTAC),derived from the supramolecular self-assembly of drug conjugates that bridge a PROTAC targeting hexokinaseⅡ(HK2)and a photosensitizer via a biomarker-cleavable linker.In a triple-negative breast cancer(TNBC)model,NanoTAC initially silences PROTAC activity and accumulates in tumor regions,where it undergoes linker cleavage in response to enzymatic biomarkers.Upon photoirradiation,PDT-induced pyroptotic cell death promotes the release of tumor-associated antigens(TAAs)and damage-associated molecular patterns(DAMPs)to drive the cancer-immunity cycle.Concurrently,targeted protein degradation(TPD)via PROTACs counteracts glucose and oxygen consumption in the TME,ultimately potentiating pyroptosis-mediated photoimmunotherapy.This combination therapy achieves a high rate of complete regression in primary TNBC and confers adaptive immunity to prevent metastasis and recurrence.Our study presents a rationally designed nanomedicine that integrates PDT and PROTACs,shedding light on strategies for more effective cancer immunotherapy.展开更多
In light of the burgeoning successes of cancer immunotherapy,glioblastoma(GBM)remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity.Thus,identifying promising the...In light of the burgeoning successes of cancer immunotherapy,glioblastoma(GBM)remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity.Thus,identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge.Here we describe photodynamic protein tyrosine phosphatase 1B(PTP1B)proteolysis mediated by a proteolysis-targeting chimera(PROTAC)nanoassembly.The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B(Cat B)-cleavable peptide,which spontaneously forms nanoassemblies due to intermolecularπ-πstack-ing interactions.In GBM models,PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier(BBB),triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage.Upon laser irradiation,photodynamic therapy(PDT)synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death(ICD)in tumor cells.Subsequently,persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers,reinvigorating their function-ality.These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cellmediated antitumor immunity as well as protective immunity,completely eradicating the primary GBM and preventing its recurrence.Overall,our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.展开更多
Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical ...Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract.Herein,we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha(TNF-α)siRNA completely.The remarkable structural stability of milk-derived exosomes(M-Exos),as opposed to those from HEK293T cells,makes them exceptional siRNA carriers.Results demonstrate that milk exosomes loaded with TNF-αsiRNA(M-Exo/siR)can effectively inhibit the expression of TNF-α-related inflammatory cytokines.Moreover,given that milk exosomes are composed of unique lipids with high bioavailability,orally administered M-Exo/siR effectively reach colonic tissues,leading to decreased TNF-αexpression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model.Hence,milk-derived exosomes carrying TNF-αsiRNA can be effectively employed to treat inflammatory bowel disease.Indeed,using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery,including siRNA.展开更多
Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predomin...Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predominant infiltrated immune cells in a tumor,play a pivotal role in regulating the immunosuppressive tumor microenvironment.As a potential therapeutic strategy to counteract TAMs,here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages.Exosomes derived from M1-type macrophages(M1-Exo)promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency.Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability,potentiating antitumor immunity surrounding the tumor.Strikingly,these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II,offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.展开更多
基金supported by grants from the National Research Foundation(NRF)of Korea,funded by the Ministry of Science(RS-2025-02219039,RS-2025-02217286,RS-2024-00351420,RS-2024-00405287,RS-2024-00463774,and RS-2021-NR061836)the Intramural Research Program of KIST.
文摘Photodynamic therapy(PDT)induces tumor cell pyroptosis,a form of programmed cell death that triggers antitumor immunity.However,high glucose metabolism and hypoxic conditions in the tumor microenvironment(TME)limit PDT efficiency and impair effector cell function.Here,we propose a cancer metabolic reprogramming-enabling photoresponsive nanoproteolysis-targeting chimera(Nano-PROTAC;NanoTAC),derived from the supramolecular self-assembly of drug conjugates that bridge a PROTAC targeting hexokinaseⅡ(HK2)and a photosensitizer via a biomarker-cleavable linker.In a triple-negative breast cancer(TNBC)model,NanoTAC initially silences PROTAC activity and accumulates in tumor regions,where it undergoes linker cleavage in response to enzymatic biomarkers.Upon photoirradiation,PDT-induced pyroptotic cell death promotes the release of tumor-associated antigens(TAAs)and damage-associated molecular patterns(DAMPs)to drive the cancer-immunity cycle.Concurrently,targeted protein degradation(TPD)via PROTACs counteracts glucose and oxygen consumption in the TME,ultimately potentiating pyroptosis-mediated photoimmunotherapy.This combination therapy achieves a high rate of complete regression in primary TNBC and confers adaptive immunity to prevent metastasis and recurrence.Our study presents a rationally designed nanomedicine that integrates PDT and PROTACs,shedding light on strategies for more effective cancer immunotherapy.
基金supported by grants from the National Research Foundation(NRF)of Korea,funded by the Ministry of Science(RS-2025-02219039,RS-2021-NR061836,RS-202400343156,NRF-2022R1A2C2006861,RS-2024-00463774,RS2022-NR068161 and RS-2024-00405287)the Intramural Research Program of KIST.
文摘In light of the burgeoning successes of cancer immunotherapy,glioblastoma(GBM)remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity.Thus,identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge.Here we describe photodynamic protein tyrosine phosphatase 1B(PTP1B)proteolysis mediated by a proteolysis-targeting chimera(PROTAC)nanoassembly.The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B(Cat B)-cleavable peptide,which spontaneously forms nanoassemblies due to intermolecularπ-πstack-ing interactions.In GBM models,PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier(BBB),triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage.Upon laser irradiation,photodynamic therapy(PDT)synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death(ICD)in tumor cells.Subsequently,persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers,reinvigorating their function-ality.These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cellmediated antitumor immunity as well as protective immunity,completely eradicating the primary GBM and preventing its recurrence.Overall,our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.
基金supported by the Bio&Medical Technology Development Program(NRF-2022M3E5F2018170)the Intramural Research Program of the Korea Institute of Science and Technology(KIST).
文摘Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract.Herein,we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha(TNF-α)siRNA completely.The remarkable structural stability of milk-derived exosomes(M-Exos),as opposed to those from HEK293T cells,makes them exceptional siRNA carriers.Results demonstrate that milk exosomes loaded with TNF-αsiRNA(M-Exo/siR)can effectively inhibit the expression of TNF-α-related inflammatory cytokines.Moreover,given that milk exosomes are composed of unique lipids with high bioavailability,orally administered M-Exo/siR effectively reach colonic tissues,leading to decreased TNF-αexpression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model.Hence,milk-derived exosomes carrying TNF-αsiRNA can be effectively employed to treat inflammatory bowel disease.Indeed,using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery,including siRNA.
基金This work was supported by the Samsung Research Funding&Incubation Center of Samsung Electronics(SRFC-MA1901-10)and the Intramural Research Program of KIST.
文摘Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predominant infiltrated immune cells in a tumor,play a pivotal role in regulating the immunosuppressive tumor microenvironment.As a potential therapeutic strategy to counteract TAMs,here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages.Exosomes derived from M1-type macrophages(M1-Exo)promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency.Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability,potentiating antitumor immunity surrounding the tumor.Strikingly,these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II,offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.
