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

• DOI: 10.1016/j.bioactmat.2024.08.013
• Publication Date: 2024-08-27T05:32:17Z
• Authors: 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
• Keywords: Autophagy inhibition; 0303 health sciences; 03 medical and health sciences; Immune escape; QH301-705.5; Multicomponent reaction; TA401-492; ROS sensitive; Biology (General); Materials of engineering and construction. Mechanics of materials; Article; Cationic nanogel

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.