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.