Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2303385120. doi: 10.1073/pnas.2303385120. Epub 2023 Aug 7.
Excessive cell-free DNA (cfDNA) in the serum and synovium is considered a causative factor of rheumatoid arthritis (RA). Thus, cfDNA scavenging by using cationic polymers has been an effective therapeutic avenue, while these stratagems still suffer from systemic toxicity and unstable capture of cfDNA. Here, inspired by the biological charge-trapping effects and active degradation function of enzyme-containing organelles in vivo, we proposed a cationic peptide dendrimer nanogel with deoxyribonuclease I (DNase I) conjugation for the treatment of RA. Benefitting from their naturally derived peptide components, the resultant nanogels were highly biocompatible. More attractively, by tailoring them with a larger size and higher surface charge density, these cationic nanogels could achieve the fastest targeting capability, highest accumulation amounts, longer persistence time, and superior DNA scavenging capacity in inflamed joints. Based on these features, we have demonstrated that the organelle mimicking cationic nanogels could significantly down-regulate toll-like receptor (TLR)-9 signaling pathways and attenuate RA symptoms in collagen-induced arthritis mice. These results make the bioinspired DNase I conjugated cationic nanogels an ideal candidate for treating RA and other immune dysregulation diseases.
血清和滑膜中过量的无细胞游离 DNA（cfDNA）被认为是类风湿关节炎（RA）的一个致病因素。因此，利用阳离子聚合物清除 cfDNA 一直是一种有效的治疗方法，而这些策略仍然存在全身毒性和 cfDNA 捕获不稳定的问题。在这里，受体内含酶细胞器的生物电荷捕获效应和主动降解功能的启发，我们提出了一种具有脱氧核糖核酸酶 I（DNase I）结合的阳离子肽树状聚合物纳米凝胶，用于治疗 RA。由于其天然衍生的肽成分，所得的纳米凝胶具有很高的生物相容性。更吸引人的是，通过将它们设计成更大的尺寸和更高的表面电荷密度，这些阳离子纳米凝胶可以在炎症关节中实现最快的靶向能力、最高的积累量、更长的持续时间和优异的 DNA 清除能力。基于这些特性，我们已经证明，细胞器模拟的阳离子纳米凝胶可以显著下调 Toll 样受体（TLR）-9 信号通路，并减轻胶原诱导性关节炎小鼠的 RA 症状。这些结果使得这种受生物启发的、具有 DNase I 结合的阳离子纳米凝胶成为治疗 RA 和其他免疫失调疾病的理想候选药物。
