Carrier-free Nanotherapeutics unleashed: Ce6/siPD-L1 co-delivery system synergizes photodynamic and RNAi therapies to combat breast cancer.

Small interfering RNA targeting PD-L1 (siPD-L1) demonstrates therapeutic potential in cancer immunotherapy, but faces challenges including inefficient lysosomal escape and carrier-induced toxicity. To address these limitations, we developed a carrier-free nanoparticle (NP) system, TPP-Ce6@siPD-L1. The amino-modified triphenylphosphine (TPP) was covalently connected with Ce6 to form an amphiphilic complex, which then loaded siPD-L1 creating an efficient co-delivery system for photosensitizers (PS) and gene drugs. Electrostatic and hydrophobic interactions drove the spontaneous self-assembly of TPP-Ce6 and siPD-L1 into uniform spherical NPs with an average diameter of 190 ± 4.885 nm, achieving siPD-L1 encapsulation and Ce6 loading. These NPs exhibited excellent structural stability in serum over 5 days and rapid cellular uptake (internalization within 2 h), outperforming free siRNA. The mitochondrial targeting of TPP-Ce6 ensures the generation of reactive oxygen species (ROS) within tumor cell mitochondria upon light irradiation, leading to mitochondrial damage and apoptosis. Simultaneously, the delivery of siPD-L1 effectively silences PD-L1 expression, enhancing immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway (cGAS-STING). This dual-modality platform integrates photodynamic therapy (PDT) and RNA interference (RNAi), offering a novel approach for synergistic anticancer therapy.