Shi Rongying, Fu Jiali, Li Min, Zhang Anqi, Huang Shiyun, Yang Xueying, Liang Yi, Quan Yuan, He Shanshan, Huang Shiqi, Li Lin, Sun Xun, Gong Tao, Zhang Ling, Lin Qing, Zhang Zhirong
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China; Sichuan Good Doctor Panxi Pharmaeceutical Co.Ltd, Xichang, Sichuan 615000, PR China.
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
J Control Release. 2025 Aug 10;384:113919. doi: 10.1016/j.jconrel.2025.113919. Epub 2025 Jun 1.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder with increasing global prevalence. Despite substantial research efforts, the exact etiology of RA remains elusive, and its pathological environment involved appears complicated. To date first-line RA therapies primarily rely on pharmacological interventions, involving chemical and biologic agents that exert systemic immunosuppressive effects or inhibit single signaling molecule blockage. However, these treatments are often associated with significant adverse effects and suboptimal responsiveness. Therefore, the quest for developing innovative RA therapeutic strategies that ensure both high efficacy and robust safety profiles remains a global challenge. In this study, inspired by the natural inflammatory tropism and favorable biocompatibility of monocyte membranes (mMc), we developed a novel platform of mMc-coated drug nanocrystals (mMc@DNCs) with an exceptional drug loading efficiency of approximately 70 %. This system co-formulated an NLRP3 inflammasome inhibitor (MCC950) alongside a reduced dose of dexamethasone (DEX), aiming to simultaneously address both the symptomatic and underlying inflammatory drivers of RA. The therapeutic potential of mMc@DNCs was evaluated in adjuvant-induced arthritis model rats. Following intravenous administration, mMc@DNCs selectively accumulated in inflamed joints, resulting in marked attenuation of joint swelling, bone erosion, and cartilage damage. Moreover, treatment with mMc@DNCs significantly suppressed the expression of pro-inflammatory cytokines TNF-α and IL-1β in the joint cavity. Importantly, this co-formulation exhibited minimal off-target toxicity, suggesting a favorable systemic safety. Hopefully through the investigation it would lay a solid foundation for the development of advanced targeted drug delivery strategies for RA, offering a promising avenue toward safer and more effective therapeutic interventions.
类风湿性关节炎（RA）是一种全球患病率不断上升的慢性自身免疫性疾病。尽管进行了大量研究，但RA的确切病因仍不清楚，其涉及的病理环境似乎很复杂。迄今为止，RA的一线治疗主要依赖于药物干预，包括具有全身免疫抑制作用或抑制单一信号分子阻断的化学和生物制剂。然而，这些治疗通常伴随着显著的不良反应和欠佳的反应性。因此，开发既能确保高效又具有强大安全性的创新RA治疗策略仍然是一项全球性挑战。在本研究中，受单核细胞膜（mMc）天然的炎症趋向性和良好的生物相容性启发，我们开发了一种新型的mMc包被药物纳米晶体（mMc@DNCs）平台，其药物负载效率高达约70%。该系统将NLRP3炎性小体抑制剂（MCC950）与降低剂量的地塞米松（DEX）共同配制，旨在同时解决RA的症状性和潜在炎症驱动因素。在佐剂诱导的关节炎模型大鼠中评估了mMc@DNCs的治疗潜力。静脉注射后，mMc@DNCs选择性地在炎症关节中积累，导致关节肿胀、骨侵蚀和软骨损伤明显减轻。此外，用mMc@DNCs治疗显著抑制了关节腔中促炎细胞因子TNF-α和IL-1β的表达。重要的是，这种联合制剂表现出最小的脱靶毒性，表明其具有良好的全身安全性。希望通过这项研究，为开发先进的RA靶向药物递送策略奠定坚实基础，为更安全、更有效的治疗干预提供一条有前景的途径。
