Bioorthogonal Click-to-Disassemble Phthalocyanine Nanoassemblies for Precise Chemo-Photodynamic Therapy against Hypoxic Tumors.

Abstract

Photodynamic therapy (PDT) offers precise spatiotemporal control over cancer treatment but remains hampered by nonspecific photosensitizer activation, oxygen dependence, and some other limitations. Herein, we report a bioorthogonal "click-to-disassemble" strategy that enables tumor-selective activation of self-assembled phthalocyanine nanoassemblies for chemo-photodynamic therapy against hypoxic tumors. An amphiphilic zinc(II) phthalocyanine bearing three triethylene glycol chains and a tetrazine-functionalized substituent spontaneously self-assembles into photodynamically silent nanoparticles through aggregation-induced quenching while simultaneously encapsulating the hypoxia-activated prodrug tirapazamine (TPZ). A bicyclo[6.1.0]non-4-yne (BCN) activator installed with an epidermal growth factor receptor (EGFR)-targeting peptide through a cathepsin B-cleavable linker selectively delivers the bioorthogonal trigger to EGFR-overexpressing cancer cells. Intracellular cleavage of the linker releases a small hydrophilic BCN moiety, which reacts rapidly with the tetrazine unit through an inverse electron-demand Diels-Alder reaction, converting the amphiphilic photosensitizer into a hydrophilic product that disrupts the nanoassemblies. This process simultaneously restores photodynamic activity and releases TPZ, which is activated by PDT-enhanced tumor hypoxia to achieve cooperative chemotherapy. The bioorthogonally triggered activation minimizes off-target phototoxicity while markedly enhancing tumor-selective therapeutic efficacy in vitro and in vivo. This work establishes bioorthogonal disassembly as a general strategy for spatiotemporal activation of self-assembled therapeutic nanomaterials and expands the toolbox of precision photomedicine.

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