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ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape
Jie Gao1,2, Yonghua Zhai3, Weihong Lu4
1Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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 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.
Insights
Novel nanogels inhibit cancer growth by blocking autophagy and preventing immune evasion. These ROS-responsive nanogels silence programmed death-ligand 1 (PD-L1) and enhance anti-tumor immunity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Autophagy inhibition is a promising cancer therapy strategy.
- Pharmacological autophagy disruption can paradoxically increase tumor immune evasion via PD-L1 upregulation.
- Novel nanocarriers are needed to overcome these limitations in cancer treatment.
Purpose of the Study:
- To develop ROS-responsive cationic nanogels for cancer therapy.
- To address PD-L1 upregulation and immune evasion caused by autophagy inhibition.
- To create an effective nanomedicine for synergistic antitumor effects.
Main Methods:
- Utilized selenol chemistry-mediated multicomponent reaction (MCR) to synthesize PEI-based nanogels.
- Incorporated low-molecular-weight PEI, γ-selenobutylacetone, and PEGMA.
- Screened AₓSeᵧO<0xE1><0xB5><0xA3> nanogels, identifying optimized A₁.₈Se₃O₀.₅/siPD-L1 nanogels for PD-L1 silencing.
Main Results:
- Optimized nanogels (approx. 200 nm) showed high colloidal stability and effective PD-L1 silencing.
- Nanogels enhanced tumor cell uptake, degraded oxidatively, and inhibited autophagy by lysosome alkalinization.
- Significant downregulation of PD-L1 and upregulation of MHC-I observed, promoting CD8⁺ T cell proliferation and reducing tumor growth.
Conclusions:
- A₁.₈Se₃O₀.₅/siPD-L1 nanogels effectively inhibit tumor growth via self-inhibition of autophagy, MHC-I upregulation, and PD-L1 downregulation.
- Dynamic diselenide bonds enable synergistic antitumor efficacy by managing autophagy and preventing immune escape.
- Developed nanogels represent a promising strategy for overcoming immune evasion in cancer therapy.
