Stimuli-Responsive Nanoplatforms for Precision Intervention in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction. While conventional pharmacotherapies form the cornerstone of RA management, their efficacy is often limited by suboptimal therapeutic outcomes and severe systemic toxicity. In this context, stimuli-responsive nanoplatforms (SR-NPs) have emerged as a promising approach for precision treatment of RA, enabling on-demand drug release triggered by disease-specific endogenous (e.g., pH, ROS, enzymes, GSH, hypoxia) or exogenous (e.g., light, ultrasound, magnetic fields, heat) cues. This review provides a systematic overview of the cutting-edge applications of SR-NPs, categorizing them into endogenous (single- and multi-stimuli), exogenous (single- and multi-stimuli), and hybrid endogenous-exogenous (e.g., ROS/pH/light, GSH/heat) responsive systems. We critically evaluate the design principles, targeting mechanisms, therapeutic payloads, and performance of each category in preclinical RA models. Our analysis reveals that endogenous systems leverage the pathological microenvironment for disease-dependent actuation, exogenous platforms offer tunable spatiotemporal control, while hybrid designs represent an emerging trend toward synergistic and programmable precision. Despite promising advances in enhanced joint retention and effective inflammation suppression, key challenges concerning stimulus heterogeneity, long-term biocompatibility, and clinical translation remain to be addressed. Taken together, this work underscores the evolution of SR-NPs into intelligent and multifaceted therapeutics, thereby providing a potential framework for personalized RA management.