Supramolecular nanoassemblies-mediated GSH depletion boosts synergistic chemo- and photodynamic therapy for immunogenicity enhancement

O2-dependent photodynamic therapy (PDT) generally suffers from compromised therapeutic efficiency due to a hypoxic tumor microenvironment. The therapeutic efficiency enhancement of PDT in a hypoxic tumor microenvironment usually requires sophisticated chemical design and multistep preparation and purification procedures. The development of a facile yet robust strategy to improve the therapeutic efficiency of PDT is thus highly desirable for clinical translations, but remains a significant challenge. For this purpose, we reported herein the use of Azobenzene (Azo) not only as conjugation sites for facile construction of multicomponent supramolecular nanomedicine based on a guest homopolymer poly(Azobenzene) (PAzo) and three β-CD-decorated host moieties, i.e., β-CD-modified photosensitizer chlorin e6 (β-CD-Ce6), chemotherapeutic drug cisplatin (β-CD-Pt(IV)), and hydrophilic poly(oligo ethylene glycol) methacrylate (β-CD-POEGMA) via host–guest interactions, but also for glutathione (GSH) depletion-enhanced synergistic chemo- and photodynamic therapy via hypoxia-triggered cleavage of Azo. Notably, the resulting self-assembled supramolecular nanoparticles (NPs) with a Ce6, platinum(IV), and POEGMA molar ratio of 8:8:2 (NPCe6/Pt) mediated greater cytotoxicity with a half maximal inhibitory concentration (IC50) value 6-fold lower than that of free Ce6 under a hypoxia condition with 660 nm laser irradiation because Azo cleavage-induced GSH depletion boosts synergistic chemo- and photodynamic therapy, which further led to immunogenicity enhancement with a tumor inhibition rate of 93.1 % in a murine 4T1 transplantation tumor model. The modularized supramolecular nanoplatform developed herein provides a facile yet robust strategy for advanced combinatory cancer therapy with great potential for clinical translations.