Liao Junyi, Zhu Zhenglin, Zou Jing, Liu Senrui, Luo Xuefeng, Bao Wei, Du Chengcheng, Lei Yiting, Huang Wei
Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing, 400016, China.
Adv Healthc Mater. 2025 Jan;14(2):e2401985. doi: 10.1002/adhm.202401985. Epub 2024 Oct 14.
Osteoarthritis (OA) is an inflammatory and progressive joint disease characterized by angiogenesis-mediated sustained, chronic, and low-grade synovitis. Anti-angiogenesis is emerging as a strategy for attenuating OA progression, but is often compromised by poor targeted drug delivery and immune clearance. Recent studies have identified macrophages formed a "protective barrier" in the lining layer (LL) of synovium, which blocked the communication of joint cavity and sublining layer (SL) of synovium. Inspired by natural mimicry, macrophage membrane-camouflaged drug delivery is explored to avoid immune clearance. Based on the single cell RNA sequencing, the CD34 synovial cells are identified as "sentinel cells" for synovium angiogenesis. Consequently, CD34 antibody-modified macrophage membrane is constructed to target new angiogenesis. Hence, a biomimetic multi-layered nanoparticle (NP) is developed that incorporates axitinib-loaded poly(lactic-co-glycolic) acid (PLGA) with CD34 antibody modified macrophage membrane (Atb@NP@Raw@CD34) to specifically deliver axitinib (Atb) to the SL and sustain inhibiting angiogenesis without immune elimination. It is found that the Atb@NP@Raw@CD34 can pass through macrophage "barrier", specifically targeting CD34 cells, continuously releasing Atb and anti-angiogenesis in OA synovitis. Furthermore, in vivo data demonstrated that Atb@NP@Raw@CD34 can attenuate joint degeneration by inhibiting synovium angiogenesis-mediated synovitis. In conclusion, local injection of Atb@NP@Raw@CD34 presents a promising approach for clinically impeding OA progression.
骨关节炎（OA）是一种炎症性进行性关节疾病，其特征是血管生成介导的持续性、慢性和低度滑膜炎。抗血管生成正成为减缓OA进展的一种策略，但往往因靶向给药不佳和免疫清除而受到影响。最近的研究发现，巨噬细胞在滑膜衬里层（LL）中形成了一个“保护屏障”，阻断了关节腔与滑膜下层（SL）之间的沟通。受自然模仿的启发，人们探索了巨噬细胞膜伪装的药物递送方式以避免免疫清除。基于单细胞RNA测序，CD34滑膜细胞被确定为滑膜血管生成的“哨兵细胞”。因此，构建了CD34抗体修饰的巨噬细胞膜以靶向新生血管。于是，开发了一种仿生多层纳米颗粒（NP），它将载有阿昔替尼的聚乳酸-乙醇酸共聚物（PLGA）与CD34抗体修饰的巨噬细胞膜相结合（Atb@NP@Raw@CD34），将阿昔替尼（Atb）特异性递送至滑膜下层并持续抑制血管生成而不被免疫清除。研究发现，Atb@NP@Raw@CD34可以穿过巨噬细胞“屏障”，特异性靶向CD34细胞，在OA滑膜炎中持续释放Atb并发挥抗血管生成作用。此外，体内数据表明，Atb@NP@Raw@CD34可以通过抑制滑膜血管生成介导的滑膜炎来减轻关节退变。总之，局部注射Atb@NP@Raw@CD34为临床上延缓OA进展提供了一种有前景的方法。
