{"title":"解码复杂微环境实现精密光疗。","authors":"Qihang Ding,Manlin Qi,Wen Li,Meiqi Li,Jiling Xu,Yujin Kim,Goeun Kim,Biao Dong,Lin Wang,Jong Seung Kim","doi":"10.1021/acs.accounts.5c00488","DOIUrl":null,"url":null,"abstract":"ConspectusThe complex and dynamic microenvironments of pathological sites, including infections, tumors, and neurological disorders, impose formidable challenges on conventional therapies due to features such as iron dysregulation, localized acidity, biofilm barriers, and thermal adaptation. Harnessing these microenvironmental cues to design light-activated, microenvironment-responsive therapeutic platforms offers a promising strategy for precise, spatiotemporally controlled treatments.Nutritional immunity restricts iron availability to suppress pathogen proliferation, while bacteria deploy specialized siderophore-mediated uptake systems to circumvent this restriction. By exploiting this vulnerability, \"Trojan horse\" nanoplatforms such as a multifunctional nanocomposite (Ga-CT@P) can hijack bacterial iron uptake pathways, induce iron starvation, and exert potent antimicrobial effects. DFT calculations revealed that Ga3+ exhibits stronger, more uniform binding to enterobactin than Fe3+, leading to stable, redox-inert complexes that mislead bacterial transport systems.Beyond metal ion interference, acid-responsive photodynamic therapy (PDT) offers spatiotemporally precise activation at infectious sites while minimizing off-target toxicity. Our development of DHTPA, a pH-responsive AIE photosensitizer, enables robust reactive oxygen species (ROS) generation exclusively under mildly acidic conditions, enhancing bactericidal efficacy. This platform demonstrated strong antibacterial effects against drug-resistant pathogens and effectively promoted wound healing in vivo, showcasing the potential of lesion-specific \"on-demand\" PDT.To address biofilm barriers, OMV-camouflaged nanodisguisers synergistically integrate photothermal heating, ion interference, and ROS generation to dismantle biofilms while inducing metabolic collapse in pathogens. Simultaneously, OMV-coated nanodisguisers exploit bacterial adhesion pathways for targeted delivery, enabling photonic disruption of pathogen metabolism.In thermosensitive microenvironments, where heat-shock-protein-mediated thermal tolerance limits photothermal therapy (PTT), we developed dual-laser PTT strategies using NIR-II AIEgens (PM331@F127) to achieve precise, stepwise thermal regulation. This strategy rapidly suppresses heat tolerance mechanisms at higher temperatures and maintains moderate thermal ablation, maximizing efficacy while reducing collateral damage.In high-barrier systems such as the central nervous system (CNS), crossing the blood-brain barrier (BBB) is essential for effective phototherapy. We designed DK@RA-PEG, an NIR-II photosensitizer platform functionalized with RVG peptides and nucleic acid aptamers, to enable BBB penetration, virus-specific targeting, and ROS-mediated viral eradication under NIR light. This approach demonstrated effective treatment of rabies virus infection in vivo while maintaining neurocompatibility.Collectively, these advances establish a versatile framework for microenvironment-responsive, light-controlled therapies that decode and harness biochemical and physical signatures within diseased tissues, achieving spatiotemporal precision beyond conventional modalities. By integrating chemical signaling modulation, smart molecular design, and physiological barrier penetration, these platforms illuminate a path toward intelligent, personalized phototherapies for complex disease landscapes.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"157 1","pages":""},"PeriodicalIF":17.7000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Precision Phototherapy Enabled by Decoding Complex Microenvironments.\",\"authors\":\"Qihang Ding,Manlin Qi,Wen Li,Meiqi Li,Jiling Xu,Yujin Kim,Goeun Kim,Biao Dong,Lin Wang,Jong Seung Kim\",\"doi\":\"10.1021/acs.accounts.5c00488\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"ConspectusThe complex and dynamic microenvironments of pathological sites, including infections, tumors, and neurological disorders, impose formidable challenges on conventional therapies due to features such as iron dysregulation, localized acidity, biofilm barriers, and thermal adaptation. Harnessing these microenvironmental cues to design light-activated, microenvironment-responsive therapeutic platforms offers a promising strategy for precise, spatiotemporally controlled treatments.Nutritional immunity restricts iron availability to suppress pathogen proliferation, while bacteria deploy specialized siderophore-mediated uptake systems to circumvent this restriction. By exploiting this vulnerability, \\\"Trojan horse\\\" nanoplatforms such as a multifunctional nanocomposite (Ga-CT@P) can hijack bacterial iron uptake pathways, induce iron starvation, and exert potent antimicrobial effects. DFT calculations revealed that Ga3+ exhibits stronger, more uniform binding to enterobactin than Fe3+, leading to stable, redox-inert complexes that mislead bacterial transport systems.Beyond metal ion interference, acid-responsive photodynamic therapy (PDT) offers spatiotemporally precise activation at infectious sites while minimizing off-target toxicity. Our development of DHTPA, a pH-responsive AIE photosensitizer, enables robust reactive oxygen species (ROS) generation exclusively under mildly acidic conditions, enhancing bactericidal efficacy. This platform demonstrated strong antibacterial effects against drug-resistant pathogens and effectively promoted wound healing in vivo, showcasing the potential of lesion-specific \\\"on-demand\\\" PDT.To address biofilm barriers, OMV-camouflaged nanodisguisers synergistically integrate photothermal heating, ion interference, and ROS generation to dismantle biofilms while inducing metabolic collapse in pathogens. Simultaneously, OMV-coated nanodisguisers exploit bacterial adhesion pathways for targeted delivery, enabling photonic disruption of pathogen metabolism.In thermosensitive microenvironments, where heat-shock-protein-mediated thermal tolerance limits photothermal therapy (PTT), we developed dual-laser PTT strategies using NIR-II AIEgens (PM331@F127) to achieve precise, stepwise thermal regulation. This strategy rapidly suppresses heat tolerance mechanisms at higher temperatures and maintains moderate thermal ablation, maximizing efficacy while reducing collateral damage.In high-barrier systems such as the central nervous system (CNS), crossing the blood-brain barrier (BBB) is essential for effective phototherapy. We designed DK@RA-PEG, an NIR-II photosensitizer platform functionalized with RVG peptides and nucleic acid aptamers, to enable BBB penetration, virus-specific targeting, and ROS-mediated viral eradication under NIR light. This approach demonstrated effective treatment of rabies virus infection in vivo while maintaining neurocompatibility.Collectively, these advances establish a versatile framework for microenvironment-responsive, light-controlled therapies that decode and harness biochemical and physical signatures within diseased tissues, achieving spatiotemporal precision beyond conventional modalities. By integrating chemical signaling modulation, smart molecular design, and physiological barrier penetration, these platforms illuminate a path toward intelligent, personalized phototherapies for complex disease landscapes.\",\"PeriodicalId\":1,\"journal\":{\"name\":\"Accounts of Chemical Research\",\"volume\":\"157 1\",\"pages\":\"\"},\"PeriodicalIF\":17.7000,\"publicationDate\":\"2025-10-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Accounts of Chemical Research\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.accounts.5c00488\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.accounts.5c00488","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Precision Phototherapy Enabled by Decoding Complex Microenvironments.
ConspectusThe complex and dynamic microenvironments of pathological sites, including infections, tumors, and neurological disorders, impose formidable challenges on conventional therapies due to features such as iron dysregulation, localized acidity, biofilm barriers, and thermal adaptation. Harnessing these microenvironmental cues to design light-activated, microenvironment-responsive therapeutic platforms offers a promising strategy for precise, spatiotemporally controlled treatments.Nutritional immunity restricts iron availability to suppress pathogen proliferation, while bacteria deploy specialized siderophore-mediated uptake systems to circumvent this restriction. By exploiting this vulnerability, "Trojan horse" nanoplatforms such as a multifunctional nanocomposite (Ga-CT@P) can hijack bacterial iron uptake pathways, induce iron starvation, and exert potent antimicrobial effects. DFT calculations revealed that Ga3+ exhibits stronger, more uniform binding to enterobactin than Fe3+, leading to stable, redox-inert complexes that mislead bacterial transport systems.Beyond metal ion interference, acid-responsive photodynamic therapy (PDT) offers spatiotemporally precise activation at infectious sites while minimizing off-target toxicity. Our development of DHTPA, a pH-responsive AIE photosensitizer, enables robust reactive oxygen species (ROS) generation exclusively under mildly acidic conditions, enhancing bactericidal efficacy. This platform demonstrated strong antibacterial effects against drug-resistant pathogens and effectively promoted wound healing in vivo, showcasing the potential of lesion-specific "on-demand" PDT.To address biofilm barriers, OMV-camouflaged nanodisguisers synergistically integrate photothermal heating, ion interference, and ROS generation to dismantle biofilms while inducing metabolic collapse in pathogens. Simultaneously, OMV-coated nanodisguisers exploit bacterial adhesion pathways for targeted delivery, enabling photonic disruption of pathogen metabolism.In thermosensitive microenvironments, where heat-shock-protein-mediated thermal tolerance limits photothermal therapy (PTT), we developed dual-laser PTT strategies using NIR-II AIEgens (PM331@F127) to achieve precise, stepwise thermal regulation. This strategy rapidly suppresses heat tolerance mechanisms at higher temperatures and maintains moderate thermal ablation, maximizing efficacy while reducing collateral damage.In high-barrier systems such as the central nervous system (CNS), crossing the blood-brain barrier (BBB) is essential for effective phototherapy. We designed DK@RA-PEG, an NIR-II photosensitizer platform functionalized with RVG peptides and nucleic acid aptamers, to enable BBB penetration, virus-specific targeting, and ROS-mediated viral eradication under NIR light. This approach demonstrated effective treatment of rabies virus infection in vivo while maintaining neurocompatibility.Collectively, these advances establish a versatile framework for microenvironment-responsive, light-controlled therapies that decode and harness biochemical and physical signatures within diseased tissues, achieving spatiotemporal precision beyond conventional modalities. By integrating chemical signaling modulation, smart molecular design, and physiological barrier penetration, these platforms illuminate a path toward intelligent, personalized phototherapies for complex disease landscapes.
期刊介绍:
Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance.
Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.