Harnessing Membrane-Targeting Photosensitizers to Evoke Ferroptosis and Pyroptosis Dual-Modal Cell Death for Antitumor Therapy

Abstract

Photodynamic therapy (PDT), a noninvasive and spatiotemporally controlled cancer treatment, often suffers from the mitochondrial or lysosomal accumulation of conventional photosensitizers (PSs), primarily triggering apoptosis and limiting efficacy against apoptosis-resistant tumors. Targeting the plasma membrane offers a promising, yet less explored, strategy to induce immunogenic cell death pathways like ferroptosis and pyroptosis, which can overcome therapeutic resistance. However, PSs capable of simultaneously targeting the plasma membrane and activating both ferroptosis and pyroptosis are scarce. Here, we present a simple and rational π-bridge engineering strategy to develop multifunctional membrane-anchored PSs. Among our synthesized compounds, TDTP exhibits strong near-infrared (NIR) fluorescence, distinct aggregation-induced emission (AIE) characteristics, superior reactive oxygen species (ROS) generation, and precise plasma membrane localization. Upon light activation, TDTP induces synergistic ferroptotic-pyroptotic cell death, leading to highly efficient tumor ablation at nanomolar concentrations (IC₅₀ = 26.07 nM). In vivo studies demonstrate that TDTP enables high-contrast NIR imaging and substantially inhibits tumor growth under image-guided PDT. This work highlights a facile yet powerful strategy for constructing membrane-specific PSs and introduces a rare class of theranostic agents capable of inducing dual cell death pathways.