Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and...Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular level.However,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date.Here,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular nanomedicines.Poly(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in macrophages.By adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles.Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over time.Based on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation timelines.More importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in cells.In summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.展开更多
As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient...As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.展开更多
基金supported by Natural Science Foundation of Beijing Municipality(L212013)National Key Research and Development Program of China(No.2022YFA1206104)+2 种基金AI+Health Collaborative Innovation Cultivation Project(Z211100003521002)National Natural Science Foundation of China(81971718,82073786,81872809,U20A20412,81821004)Beijing Natural Science Foundation(7222020).
文摘Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular level.However,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date.Here,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular nanomedicines.Poly(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in macrophages.By adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles.Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over time.Based on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation timelines.More importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in cells.In summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.
基金Natural Science Foundation of Beijing Municipality(L212013)AI+Health Collaborative Innovation Cultivation Project(Z211100003521002)National Natural Science Foundation of China(82073786,81872809,U20A20412,81821004).
文摘As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.
