Molecular Engineering of Plasma Membrane and Mitochondria Dual-Targeted NIR-II AIE Photosensitizer Evoking Synergetic Pyroptosis and Apoptosis.

Phototherapy provides a noninvasive and spatiotemporal controllable paradigm to inhibit the evasion of the programmed cell death (PCD) of tumors. However, conventional photosensitizers (PSs) often induce a single PCD process, resulting in insufficient photodamage and severely impeding their application scopes. In this study, molecular engineering is conducted by adjusting electron donors to develop an aggregation-induced NIR-II emissive PS (DPITQ) for plasma membrane and mitochondria dual-targeted hypoxic tumor therapy by evoking synergetic pyroptosis and apoptosis. DPITQ displays boosted type I and II reactive oxygen species generation as well as a high photothermal conversion efficacy (43%) after laser irradiation of 635 nm. The excellent biocompatibility and appropriate lipophilicity helps the DPITQ to specifically anchor in the plasma membrane and mitochondria of cancer cells in intricate biological scenarios. Furthermore, the photosensitized DPITQ could disrupt the intact plasma membrane and cause mitochondrial dysfunction, ultimately causing concurrent pyroptosis and apoptosis to suppress cancer cell proliferation even under hypoxia. It is noteworthy that the DPITQ nanoparticles (NPs) presented clear NIR-II fluorescence imaging capability on the venous vessels of nude mice. Notably, the DPITQ NPs exerted efficient NIR-II fluorescence imaging-guided phototherapy both in multicellular tumor spheroids and in vivo, causing maximum destruction to tumors but minimum adverse effects to normal tissue. This article is protected by copyright. All rights reserved.