Oleic acid modification enables lysosomal escape of phthalocyanine photosensitizer for effective bladder cancer treatment.

Lysosomal sequestration, driven by acidic hydrolases, degrades and inactivates therapeutics, severely compromising their efficacy. While unsaturated fatty acid (UFA) modifications confer robust lysosomal escape capabilities to nanomedicines, their utility in small-molecule drug design remains largely underexplored. Capitalizing on the unique structural attributes of UFA side chains, we designed and synthesized three zinc phthalocyanine (ZnPc) conjugates featuring distinct linker architectures with oleylamine (OA): ZnPc-OA (linker-free), ZnPc-PEG2-OA (PEG linker), and ZnPc-butyl-OA (alkyl chain linker). Crucially, the linker-free ZnPc-OA demonstrated superior lysosomal escape and potent photodynamic cytotoxicity, achieving a half-maximal inhibitory concentration (IC50) of 0.176 μM. In an orthotopic non-muscle-invasive bladder cancer (NMIBC) mouse model, ZnPc-OA-mediated photodynamic therapy (PDT) exhibited robust in vivo therapeutic efficacy, rivaling that of the first-line chemotherapeutic mitomycin C (MMC). Ultimately, this work presents a compelling structural engineering strategy to circumvent lysosomal sequestration in small molecules, offering an innovative therapeutic paradigm for bladder cancer management.