Nanomaterial-based therapeutic strategies for systemic autoimmune rheumatic diseases: from molecular mechanisms to preclinical translation

Abstract

Systemic autoimmune rheumatic diseases (SARDs) are chronic, heterogeneous disorders in which loss of immune tolerance, persistent inflammation, and tissue-specific injury can culminate in irreversible organ damage and fibrosis. Although glucocorticoids, conventional immunosuppressants, biologics, and targeted small molecules have transformed care, long-term treatment remains constrained by systemic toxicity, incomplete tissue selectivity, variable response, and limited ability to restore immune homeostasis. Nanomedicine provides a modular framework for improving pharmacokinetics, concentrating therapeutics in diseased tissues, enabling controlled release, and co-delivering immunoregulatory cargos. In this Review, we focus on major SARDs—rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and lupus nephritis (LN), systemic sclerosis (SSc), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM)—while using selected evidence from adjacent immune-mediated diseases only when it provides transferable engineering or mechanistic lessons. We critically distinguish passive accumulation from demonstrated target engagement, cargo-mediated effects from intrinsic nanomaterial bioactivity, and reduction of collagen deposition from direct mechanistic evidence of antifibrotic action. We also emphasize that acidic pH, reactive oxygen species (ROS), and matrix metalloproteinase (MMP) activity are not universal SARD features but disease-, organ-, stage-, and patient-dependent variables that require quantitative validation before being used as release triggers. Recent single-cell studies further show that macrophage states form disease- and tissue-specific continua rather than a binary M1/M2 system, requiring more precise cellular endpoints. Translation of SARD nanotherapeutics will depend less on adding engineering complexity than on demonstrating disease-relevant biodistribution, target engagement, physiologically validated responsiveness, causal mechanism, repeated-dose safety, scalable manufacturing, and regulatory-quality characterization. A disease-adapted, author-proposed framework of complementary evidence domains may support more transparent assessment of preclinical nanoplatforms, without implying a validated linear pathway to clinical use.