Controllable Regulation of Ag2S Quantum‐Dot‐Mediated Protein Nanoassemblies for Imaging‐Guided Synergistic PDT/PTT/Chemotherapy against Hypoxic Tumor

Abstract The combination of phototherapy and chemotherapy holds great potential for cancer treatment, while hypoxia in tumor as well as unexpected drug release largely restricts anticancer therapy. Inspired by the natural intelligence, herein, for the first time, a “bottom‐up” protein self‐assembly strategy mediated by near‐infrared (NIR) quantum dots (QDs) with multicharged electrostatic interactions is presented to develop a tumor microenvironment (TME)‐responsive theranostic nanoplatform for imaging‐guided synergistic photodynamic therapy (PDT)/photothermal therapy (PTT)/chemotherapy. Catalase (CAT) possesses diverse surface charge distribution under different pH conditions. After modification by chlorin e6 (Ce6), the formulated CAT–Ce6 with patchy negative charges can be assembled with NIR Ag 2 S QDs by regulating their electrostatic interactions, allowing for effective incorporation of specific anticancer drug oxaliplatin (Oxa). Such Ag 2 S@CAT–Ce6@Oxa nanosystems are able to visualize nanoparticle (NP) accumulation to guide subsequent phototherapy, together with significant alleviation of tumor hypoxia to further enhance PDT. Moreover, the acidic TME triggers controllable disassembly through weakening the CAT surface charge to disrupt electrostatic interactions, allowing for sustained drug release. Both in vitro and in vivo results demonstrate remarkable inhibition of colorectal tumor growth with a synergistic effect. Overall, this multicharged electrostatic protein self‐assembly strategy provides a versatile platform for realizing TME‐specific theranostics with high efficiency and safety, promising for clinical translation.

摘要 光疗和化疗联合治疗癌症具有巨大的潜力，但肿瘤缺氧和药物意外释放在很大程度上限制了抗癌治疗。受自然智能的启发，本文首次提出了由具有多电荷静电相互作用的近红外（NIR）量子点（QD）介导的“自下而上”蛋白质自组装策略，以开发用于成像引导的协同光动力疗法（PDT）/光热疗法（PTT）/化疗的肿瘤微环境（TME）响应性治疗诊断纳米平台。过氧化氢酶（CAT）在不同pH条件下具有不同的表面电荷分布。经过二氢卟酚 e6 (Ce6) 修饰后，配制的带有斑片负电荷的 CAT-Ce6 可以通过调节静电相互作用与 NIR Ag 2 S QD 组装，从而有效掺入特定抗癌药物奥沙利铂 (Oxa)。这种Ag 2 S@CAT–Ce6@Oxa纳米系统能够可视化纳米颗粒（NP）的积累，以指导后续的光疗，同时显着缓解肿瘤缺氧，进一步增强PDT。此外，酸性 TME 通过削弱 CAT 表面电荷来破坏静电相互作用，从而触发可控分解，从而实现药物的持续释放。体外和体内结果均显示出对结直肠肿瘤生长的显着抑制作用，并具有协同作用。总体而言，这种多电荷静电蛋白自组装策略为实现高效、安全的 TME 特异性治疗诊断提供了一个多功能平台，有望用于临床转化。