Specifically inhibiting the proliferation of activated macrophages and clearing the high levels of reactive oxygen species (ROS) secreted by macrophages is crucial for osteoarthritis (OA) treatment. Moreover, if the clearance of these high levels of ROS can be simultaneously used to induce oxidation-responsive release of anti-inflammatory drugs, the therapeutic effect of OA may be further improved. Here, a multifunctional anti-inflammatory drug (CPHs) based on a peptide dendrimer nanogel was constructed by physically encapsulating CORM-401 and wrapping its surface with folic acid (FA)-modified hyaluronic acid (HA). CPHs is capable of efficiently entering activated macrophages via FA- and HA-mediated specific targeting effects and then rapidly release large amounts of CO by massive consumption of H₂O₂. The generated CO effectively suppresses the secretion of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by inhibiting cell proliferation; inducing the activation of heme oxygenase (HO-1), and downregulating the expression of p38 MAPK, NF-kB (p50/p65) and TLR-2. In vivo experiments further confirmed that CPHs can massively deplete ROS in OA joints and effectively suppress the degradation of articular cartilage and their extracellular matrix. More importantly, CPHs is non-toxic to normal macrophages, and the high levels of CO generated in the joints do not result in notable changes in the HbCO levels in blood. Together, these results show that CPHs is an effective and safe anti-inflammatory drug and has essential application prospects in OA treatment.

特异性抑制活化的巨噬细胞的增殖并清除巨噬细胞分泌的高水平的活性氧（ROS）对于骨关节炎（OA）的治疗至关重要。而且，如果这些高水平ROS的清除率可同时用于诱导抗炎药的氧化反应性释放，则OA的治疗效果可进一步提高。在这里，通过物理封装CORM-401并用叶酸（FA）修饰的透明质酸（HA）包裹其表面，构建了基于肽树状聚合物纳米凝胶的多功能抗炎药（CPH）。CPH能够通过FA和HA介导的特异性靶向作用有效进入活化的巨噬细胞，然后通过大量消耗H ₂ O迅速释放大量CO。₂。产生的CO通过抑制细胞增殖，有效抑制白介素（IL）-1β，IL-6和肿瘤坏死因子（TNF）-α的分泌。诱导血红素加氧酶（HO-1）活化，并下调p38 MAPK，NF-kB（p50 / p65）和TLR-2的表达。体内实验进一步证实，CPHs可大量消耗OA关节中的ROS，并有效抑制关节软骨及其细胞外基质的降解。更重要的是，CPH对正常的巨噬细胞无毒，并且在关节中产生的高水平的CO不会导致血液中HbCO水平的显着变化。总之，这些结果表明，CPH是一种有效且安全的抗炎药，在OA治疗中具有重要的应用前景。