Rational Design of Poly(disulfide) Orchestrates Thiol‐Mediated and Light‐Driven siRNA Delivery for Cancer Immunotherapy

Therapeutic siRNA application is limited by its endosomal entrapment and subsequent degradation. Here, we rationally develop a dual-pathway polymeric carrier, PFCPD, by co-assembling two functional cell-penetrating poly(disulfide)s (CPDs): PCPD, bearing a photosensitizer, and FCPD, modified with a folate-targeting ligand. This hybrid design enables efficient siRNA delivery by combining thiol-mediated membrane penetration, which facilitates direct cytosolic transport via disulfide exchange at the cell surface, and photochemical internalization (PCI), allowing endocytosed complexes to escape from endo/lysosomes upon light-triggered reactive oxygen species (ROS) generation. Simultaneously, intracellular glutathione (GSH) cleaves the polymer backbone to release siRNA and is consumed in the process, sensitizing cells to oxidative damage. When loaded with anti-GPX4 siRNA (siGPX4), PFCPD induces potent ferroptosis by downregulating GPX4 and amplifying ROS stress under illumination. The combination of ferroptosis and type I photodynamic therapy synergistically triggers immunogenic cell death, promotes dendritic cell maturation, and activates CD8+ T cell-mediated antitumor immunity in bilateral tumor models. This work presents a CPD-based siRNA nanoplatform that uniquely integrates thiol-mediated cytosolic entry with PCI-assisted endosomal escape in a single system, addressing the trade-off between tumor targeting and cytosolic accessibility. It offers a versatile strategy for siRNA delivery capable of achieving efficient cancer therapy.