Backbone flexibility/amphiphilicity modulation of AIE active polyelectrolytes for mitochondria- and nucleus-targeted synergistic photodynamic therapy of cancer cells

Mitochondria- and nucleus-targeted photodynamic therapy (PDT) to locally destruct organelles that play vital roles in physiologic processes holds great promise. Notably, the emerging polymeric photosensitizers with multiple photosensitizer units concentratedly linked in a molecular backbone could locally generate a high density of therapeutic ROS, but they normally suffer from either aggregation-caused quenching or the lack of organelle-targeting capability due the highly rigid backbone induced endosomal entrapment and incompatibility with the lipophilic organelle membranes. Herein, aggregation-induced emission (AIE) active organelle targeting polyelectrolytes (S4, S6, D4 and D6) are synthesized via integrating triphenylamine and lipophilic pyridinium into polymer backbones. Through balancing the hydrophilicity, flexibility, charge density and conjugation length, the AIE polyelectrolytes exhibit precise targeting of mitochondria/nucleus, strong ROS generation and effective PDT efficacy. Importantly, the difference in the targeting capability of mitochondria and nucleus for S4 and D4, respectively, should be attributed to their distinctive molecular flexibility/amphiphilicity instead of the zeta potential variation of the AIE polyelectrolyte nanoparticles. By simply blending S4 and D4 nanoparticles, the hybrid nanosystem S4 + D4 is formulated with dual mitochondria- and nucleus-targeting capability and a potent IC₅₀ value of 1.58 μM under white light irradiation (70 mW cm⁻², 5 min) on U87 cancer cells, which is much lower than that of control groups treated with S4 or D4 alone. This work might open up an avenue to highly efficient synergistic multiple-organelle-targeted therapeutics.