Engineered “lock-and-release” Nanomicelles for co-delivery of triptolide and Calycosin to ameliorate rheumatoid arthritis by regulating macrophage polarization

Macrophage polarization imbalance is closely implicated in the pathogenesis of rheumatoid arthritis (RA). Triptolide (TP) can effectively regulate macrophage polarization but is severely limited by its high toxicity and narrow therapeutic window. Calycosin (CAL) not only alleviates TP-induced toxicity but also exhibits anti-inflammatory and chondroprotective effects, making their combination a promising strategy for safer and more effective RA therapy. However, this free combined therapy suffers from high dosage requirements and nonspecific systemic distribution in vivo . Herein, we developed a high drug-loading, lesion-targeted, and stimuli-responsive delivery system for co-delivery of TP and CAL. Using polyamidoamine (PAMAM) as the carrier, we fabricated a locked (LD)-type folate-targeted PAMAM nanomicelle (LD-PAMAM-TP&CAL) by coating a matrix metalloproteinases (MMPs)-responsive detachable PEG shell, based on MMPs overexpression in RA microenvironment. This engineered nanomicelle showed uniform morphology, high encapsulation efficiency, and MMPs-triggered conversion from a locked (LD) state to an open state for intelligent drug release. In vitro , it achieved folate receptor (FR)-mediated targeted macrophage uptake, regulated M1/M2 polarization, protected chondrocytes, and effectively resolved the toxicity-efficacy paradox of TP. In vivo , it significantly enhanced drug accumulation in arthritic joints, alleviated joint swelling and bone destruction in CIA rats, modulated inflammatory and bone-related factor expression, balanced synovial macrophage function, and ensured systemic safety. Collectively, this “Lock-and-Release” nanomicelle integrates functional carrier innovation, drug synergy, and inflammatory microenvironment-responsive intelligent lock-to-release behavior. It successfully overcomes the clinical bottlenecks of TP and enables high-efficiency, low-toxicity RA therapy via regulating macrophage polarization, providing a promising functional nanoplatform for clinical RA treatment.