Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy

Yiqun Wu; Zhongshi Wang; Yu Ge; Ying Zhu; Tianli Tian; Jun Wei; Yu Jin; Yi Zhao; Qiang Jia; Jun Wu; Liang Ge

doi:10.1016/j.jconrel.2024.05.021

Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy

J Control Release. 2024 May 16:370:747-762. doi: 10.1016/j.jconrel.2024.05.021. Online ahead of print.

Authors

Yiqun Wu¹, Zhongshi Wang², Yu Ge¹, Ying Zhu³, Tianli Tian¹, Jun Wei¹, Yu Jin¹, Yi Zhao⁴, Qiang Jia⁵, Jun Wu⁶, Liang Ge⁷

Affiliations

¹ State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
² State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China; Department of Pharmacy, The Affiliated Hospital of Nantong University, Jiangsu 226006, China.
³ Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, China.
⁴ School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
⁵ Guangzhou City Polytechnic, Guangzhou, Guangdong 510520, China.
⁶ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou 510120, China; Bioscience and Biomedical Engineering Thrust, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou 511458, China; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, SAR 999077, China. Electronic address: junwuhkust@ust.hk.
⁷ State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: Geliang1981@hotmail.com.

PMID: 38740094
DOI: 10.1016/j.jconrel.2024.05.021

Abstract

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Keywords: Bismuthene nanosheets; Gene therapy; Immune modulation; Phototherapy; Rheumatoid arthritis; pH sensitive injectable hydrogel.