Photoactivatable Prodrug-Backboned Polymeric Nanoparticlesfor Efficient Light-Controlled Gene Delivery and Synergistic Treatmentof Platinum-Resistant Ovarian Cancer

Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt­(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c‑fos)) for light-controlled si­(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c‑fos) generates oxygen-independent N3• with mild oxidation energy for efficient endo/lysosomal escape through N3•-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt­(IV) prodrug activation, CNPPtCP/si(c‑fos) dissociates to release active Pt­(II) and unpack si­(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c‑fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.