A Trojan Horse Delivery Vehicle Carrying siRNA Nanotherapeutics with Multiple Tumor Microenvironment Responsiveness Elicits Robust Antitumor Immune Responses In Situ via a "Self-Synergistic" Approach.

The potential of small interfering RNAs (siRNAs) in the treatment of malignant tumors has attracted increasing attention due to their inherent advantages. However, their therapeutic performance strongly depends on the efficiency of their cytoplasmic delivery in vivo by the delivery vehicle with good cellular permeability and histocompatibility. Herein, a polycationic carrier camouflaged with macrophage membrane (MPM) is constructed biomimetically, which is condensed from endogenous spermine monomers through diselenide bonds. The developed Trojan horse delivery vehicle has desirable compression efficacy for siRNA oligo against PD-L1 (siPDL1) as well as intracytoplasmic release properties derived from its sequential degradation triggered by redox microenvironment in tumor cells. Furthermore, the coloading of photosensitizer can mediate photodynamic therapy (PDT) accompanied by the generation of reactive oxygen species (ROS) upon light irradiation applied, which accelerated the degradation of the carrier as well as the release of cargoes while enhancing the PD-L1 blockage-mediated immunotherapy by inducing in-situ immunogenic cell death. Moreover, the synchronously delivered siPDL1 attenuated the ROS-induced increase in immunosuppressive PD-L1 expression, thereby effectively eliciting a robust antitumor immune response with a "self-synergistic" manner in the xenograft breast cancer mouse model.