ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape

In the field of cancer therapy, inhibiting autophagy has emerged as a promising strategy. However, pharmacological disruption of autophagy can lead to the upregulation of programmed death-ligand 1 (PD-L1), enabling tumor immune evasion. To address this issue, we developed innovative ROS-responsive cationic poly(ethylene imine) (PEI) nanogels using selenol chemistry-mediated multicomponent reaction (MCR) technology. This procedure involved simple mixing of low-molecular-weight PEI (LMW PEI), γ-selenobutylacetone (γ-SBL), and poly(ethylene glycol) methacrylate (PEGMA). Through high-throughput screening, we constructed a library of AxSeyOz nanogels and identified the optimized A1.8Se3O0.5/siPD-L1 nanogels, which exhibited a size of approximately 200 nm, excellent colloidal stability, and the most effective PD-L1 silencing efficacy. These nanogels demonstrated enhanced uptake by tumor cells, excellent oxidative degradation ability, and inhibited autophagy by alkalinizing lysosomes. The A1.8Se3O0.5/siPD-L1 nanogels significantly downregulated PD-L1 expression and increased the expression of major histocompatibility complex class I (MHC-I), resulting in robust proliferation of specific CD8+ T cells and a decrease in MC38 tumor growth. As a result, the A1.8Se3O0.5/siPD-L1 nanogels inhibited tumor growth through self-inhibition of autophagy, upregulation of MHC-I, and downregulation of PD-L1. Designed with dynamic diselenide bonds, the A1.8Se3O0.5/siPD-L1 nanogels showed synergistic antitumor efficacy through self-inhibition of autophagy and prevention of immune escape. A library of ROS-responsive cationic nanogels is constructed using a facile selenol chemistry-mediated multicomponent reaction (MCR) strategy for high-throughput screening of siPD-L1 delivery. The optimized selenide/diselenide contained cationic nanogel delivery system demonstrates synergistic effects on enhancing antitumor efficacy through self-inhibition of autophagy, upregulation of MHC-I, and downregulation of PD-L1. [Display omitted] •ROS-sensitive cationic hydrogels are directly prepared on a large scale through selenol chemistry-mediated MCR technology.•The most stable nanogels with the strongest PD-L1 silencing effect are identified through high-throughput screening.•The delivery system enhances antitumor efficacy by inhibiting autophagy, upregulation of MHC-I, and downregulation of PD-L1.