A Microneedle Patch Delivers Mitochondria‐ and Lysosomes‐ Dual Targeting Prodrug‐Like Photosensitizers with Regulated Photoactivity for Precise Photodynamic Therapy

Antitumor photodynamic therapy (PDT) faces huge challenges as selectivity and phototoxic damage, requiring delivery photosensitizers (PSs) to specifically accumulate in tumors even in organelle, and avoid the phototoxic damage during delivery. Herein, a microneedle patch (AIE-mito-TPP@MN) containing mitochondria- and lysosomes- dual targeting prodrug-like PSs (AIE-mito-TPP/AlPcSNa4) that is self-assembled by mitochondria-targeted aggregation-induced-emission molecule (AIE-mito-TPP) and lysosome-targeted aluminum phthalocyanine tetrasulfonate (AlPcSNa4), is developed to achieve cancer-cell-organelle-specific targeting delivery for precise PDT with high selectivity and low phototoxic damage. AIE-mito-TPP/AlPcSNa4 displays prodrug-like activity via the regulated photoactivity to reduce the phototoxic damage caused by the "always on" PSs. Meanwhile, AIE-mito-TPP/AlPcSNa4@MN can insert into the epidermis to achieve rapid AIE-mito-TPP/AlPcSNa4 delivery in tumor lesion, and enhance selective accumulation in tumor cells. The higher lysosomal acidity in tumor cells facilitates AIE-mito-TPP/AlPcSNa4 disassembly and promotes targeting. Under light irradiation, AIE-mito-TPP/AlPcSNa4@MN impairs mitochondrial and lysosomal function to induce deeper tumor cells apoptosis at a low dose (≈6 µg), presenting greater therapeutic efficacy than AIE-mito-TPP@MN, AlPcSNa4@MN, or intravenous injection. Moreover, AIE-mito-TPP/AlPcSNa4@MN presents good biocompatibility as lower accumulation and targeting in normal cells, as well as the regulated photoactivity of prodrug-like PSs. Therefore, the dual organelle-targeting microneedle possesses great potential for precise PDT with high selectivity.