Spatiotemporally Cascade-Releasing Polyester Nanoparticles for Synergistic Photodynamic/Chemo/Gene Therapy of Colorectal Cancer.

The efficacy of cancer therapies is often limited by inefficient drug delivery due to the highly heterogeneous tumor microenvironment (TME) and various cellular resistances, such as uptake and lysosomal escape. To overcome these challenges, we designed and synthesized three integrated polyesters through BODIPY-initiated ring-opening block copolymerization, BSN-BSN, which incorporate an SN38 prodrug and a cationic positively charged ([12]aneN) unit. The optimized polyester BSN was co-assembled with DOPE, DSPE-PEG-iRGD, and Bcl-2-siRNA into multifunctional nanoparticles, BSN-DR/Bcl-2 siRNA NPs. This system achieves spatiotemporally controlled activation within tumors through iRGD-mediated targeting for enhanced cellular uptake, followed by 660 nm light-triggered photochemical internalization (PCI) to enable lysosomal escape, as well as high GSH/esterase-triggered disassembly of NPs for sequential release of siRNA and SN38. The combination of Bcl-2 protein silencing, chemotherapy, and PDT led to significant tumor growth inhibition at 95% in vivo in HCT116 models, without observable systemic toxicity. This work not only presents a novel cascade-responsive combination strategy to overcome the limitations of monotherapy and physical combination of different therapeutic components but also offers valuable experimental evidence and theoretical support for the development of highly efficient and safe polymeric nanodrugs.