pH-sensitive cationic nanoparticles for endosomal cell-free DNA scavenging against acute inflammation

Yilin Feng; Cong Wei; Yanrong Gu; Hong Zhang; Lixin Liu; Yongming Chen; Tianyu Zhao

doi:10.1016/j.jconrel.2024.03.003

pH-sensitive cationic nanoparticles for endosomal cell-free DNA scavenging against acute inflammation

J Control Release. 2024 Mar 25:369:88-100. doi: 10.1016/j.jconrel.2024.03.003. Online ahead of print.

Authors

Yilin Feng¹, Cong Wei¹, Yanrong Gu¹, Hong Zhang², Lixin Liu³, Yongming Chen⁴, Tianyu Zhao⁵

Affiliations

¹ School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China.
² Department of Biomedical Engineering, Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China.
³ School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China; Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China.
⁴ School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China; Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China; Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; College of Chemistry and Molecular Science, Henan University, Zhengzhou, China. Electronic address: chenym35@mail.sysu.edu.cn.
⁵ School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: zhaoty25@mail.sysu.edu.cn.

PMID: 38471640
DOI: 10.1016/j.jconrel.2024.03.003

Abstract

Cell-free DNA (cfDNA) released from dead cells could be a player in some autoimmune disorders by activating Toll-like receptor 9 (TLR9) and inducing proinflammatory cytokines. Cationic nanoparticles (cNPs) address cfDNA clearance, yet challenges persist, including toxicity, low specificity and ineffectiveness against endocytosed cfDNA. This study introduced pH-sensitive cNPs, reducing off-target effects and binding cfDNA at inflammatory sites. This unique approach inhibits the TLR9 pathway, offering a novel strategy for inflammation modulation. Synthesized cNPs, with distinct cationic moieties, exhibit varied pKa values, enhancing cfDNA binding. Comprehensive studies elucidate the mechanism, demonstrating minimal extracellular binding, enhanced endosomal DNA binding, and optimal tumor necrosis factor-α suppression. In a traumatic brain injury mice model, pH-sensitive cNPs effectively suppress inflammatory cytokines, highlighting their potential in acute inflammation regulation.

Keywords: Cationic nanoparticles; Inflammation regulation; Polycaprolactone; pH-sensitive.