ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape
Jie Gao, Yonghua Zhai, Weihong Lu, Xianghe Jiang, Jingsheng Zhou, Lili Wu, Longhai Du, Chunqing Ou, Xinyi Zhang, Hanliang He, Jian Zhu, Zhengbiao Zhang, Meiyun Li, Yan Wu, Xiangqiang Pan
Abstract
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 A x Se y O z nanogels and identified the optimized A 1.8 Se 3 O 0.5 /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 A 1.8 Se 3 O 0.5 /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 A 1.8 Se 3 O 0.5 /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 A 1.8 Se 3 O 0.5 /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. • 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.