Precision Phototherapy Enabled by Decoding Complex Microenvironments.

IF 17.7 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Qihang Ding,Manlin Qi,Wen Li,Meiqi Li,Jiling Xu,Yujin Kim,Goeun Kim,Biao Dong,Lin Wang,Jong Seung Kim
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引用次数: 0

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.
解码复杂微环境实现精密光疗。
包括感染、肿瘤和神经系统疾病在内的病理部位的复杂和动态微环境,由于铁调节失调、局部酸性、生物膜屏障和热适应等特征,给传统治疗带来了巨大的挑战。利用这些微环境线索来设计光激活、微环境响应的治疗平台,为精确、时空控制的治疗提供了一种有希望的策略。营养免疫限制铁的可用性来抑制病原体的增殖,而细菌部署专门的铁载体介导的摄取系统来规避这种限制。通过利用这一漏洞,“特洛伊木马”纳米平台,如多功能纳米复合材料(Ga-CT@P)可以劫持细菌铁摄取途径,诱导铁饥饿,并发挥有效的抗菌作用。DFT计算显示,与Fe3+相比,Ga3+与肠杆菌蛋白的结合更强、更均匀,从而形成稳定的氧化还原惰性复合物,误导细菌运输系统。除了金属离子干扰外,酸反应光动力疗法(PDT)在感染部位提供时空精确的激活,同时最大限度地减少脱靶毒性。我们开发的DHTPA是一种ph响应型AIE光敏剂,能够在温和的酸性条件下产生强大的活性氧(ROS),增强杀菌效果。该平台对耐药病原体具有较强的抗菌作用,并在体内有效促进伤口愈合,显示了病变特异性“按需”PDT的潜力。为了解决生物膜障碍,omv伪装的纳米伪装剂协同整合光热加热、离子干扰和ROS生成,在诱导病原体代谢崩溃的同时拆除生物膜。同时,omv涂层的纳米伪装剂利用细菌粘附途径进行靶向递送,从而实现病原体代谢的光子破坏。在热敏微环境中,热休克蛋白介导的热耐受性限制了光热治疗(PTT),我们使用NIR-II AIEgens (PM331@F127)开发了双激光PTT策略,以实现精确的、逐步的热调节。该策略在较高温度下迅速抑制耐热机制,并保持适度的热消融,最大限度地提高功效,同时减少附带损伤。在高屏障系统中,如中枢神经系统(CNS),通过血脑屏障(BBB)是有效光疗的必要条件。我们设计了一个NIR- ii光敏剂平台DK@RA-PEG,该平台由RVG肽和核酸适配体功能化,可以在近红外光下穿透血脑屏障,实现病毒特异性靶向和ros介导的病毒根除。这种方法证明了在保持神经相容性的同时有效治疗狂犬病病毒感染。总的来说,这些进展为微环境响应、光控疗法建立了一个通用框架,可以解码和利用病变组织内的生化和物理特征,实现超越传统模式的时空精度。通过整合化学信号调节、智能分子设计和生理屏障渗透,这些平台为复杂疾病景观的智能、个性化光疗法指明了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
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.
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