A dual-mode recognition strategy to enhance the lysosome-targeted bursting of PPa for efficient photodynamic cancer therapy

Photodynamic therapy (PDT) employs lasers to activate photosensitizers, generating reactive oxygen species (ROS) for tumor cell destruction. However, the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency. Recent studies have shown that lysosome-targeted PDT can directly disrupt the “explosive depot” of tumor cells by triggering the release of abundant hydrolases from lysosomes. Nevertheless, existing lysosome-targeted strategies rely predominantly on a single protonation mechanism, resulting in low targeted efficiency. To enhance lysosome-targeted bursting, this study adopted a dual-mode recognition strategy, combining “hydrophobic interaction-aided fusion” with “charge-directed anchoring”. Specifically, pyropheophorbide-a (PPa) was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths (C1, C4, C8, and C12), yielding lysosome-targeted bursting photosensitizers (PPa1, PPa4, PPa8, and PPa12). Self-assembled nanoparticles (LPPa NPs) were then prepared to facilitate tumor delivery. The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency, lysosomal targeted capability, and assembly stability of LPPa NPs. Notably, PPa4 NPs demonstrated superior cellular uptake, enhanced ROS generation, and effective lysosome-targeted bursting, thereby markedly improving antitumor efficacy. In summary, the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.