Table 2.

Evidence-status-stratified nanotherapeutic strategies and proposed applications across core SARDs.

Disease	Dominant pathological features	Evidence status and disease-specific nanotherapeutic strategies	Principal cellular/molecular targets	Main therapeutic functions	Key translational considerations
Rheumatoid arthritis (RA)	Persistent synovitis; activated endothelium; heterogeneous macrophage states; fibroblast-like synoviocyte (FLS) expansion; oxidative stress; cartilage and bone damage	DEMONSTRATED IN RA MODELS: membrane/ligand-engineered and nucleic-acid nanocarriers, selected stimuli-responsive systems, and local depots (Refs. 25, 31, 34–36). Evidence varies by formulation and endpoint.	Activated endothelium; pathogenic macrophage states; FLS; NF-κB/NLRP3/MAPK/redox networks	Increase synovial exposure; suppress inflammatory and stromal activation; reduce cytokine/inflammasome signaling; protect cartilage and bone	Quantitative joint and cell-subset biodistribution; receptor/target-engagement controls; chronic arthritis models; repeated-dose safety
Systemic lupus erythematosus/lupus nephritis (SLE/LN)	Loss of tolerance; autoreactive lymphocytes; autoantibodies and immune complexes; interferon/inflammatory signaling; glomerular and tubulointerstitial injury	DEMONSTRATED IN SLE/LN MODELS: biomimetic carriers, renal/glomerular-directed liposomes and engineered EV formulations (Refs. 30, 39, 40); not validated across all lupus manifestations.	Renal immune compartments; glomerular targets; Treg/Tfh/B-cell networks; ROS and inflammatory pathways	Improve renal or systemic drug exposure; reduce immune-complex-associated and oxidative injury; restore immune regulation; preserve renal function	Compartment-resolved renal biodistribution; glomerular target engagement; systemic-versus-renal efficacy; background immunosuppression; repeated-dose immune safety
Systemic sclerosis (SSc)	Vascular injury; immune activation; fibroblast and myofibroblast state transitions; extracellular-matrix accumulation; organ-specific fibrosis	DEMONSTRATED IN SSc MODELS: selected mRNA-LNP and engineered EV platforms with antifibrotic readouts (Refs. 41, 42). Local hydrogels and microneedles remain investigational extensions.	TRAF6/NF-κB; TGF-β/SMAD; fibroblast-state transitions; oxidative stress; immune–stromal coupling	Suppress inflammatory–fibrotic coupling and myofibroblast activation; reduce matrix synthesis; support tissue repair and organ function	Mechanistic antifibrotic endpoints beyond collagen; skin plus internal-organ models; tissue function; long-term accumulation and safety
Sjögren’s disease (SjD)	Glandular epithelial injury; B-cell-rich immune niches; interferon activity; salivary/lacrimal barrier dysfunction	PROPOSED/NOT ESTABLISHED IN SjD: gland-retentive or gland-targeted carriers, immunomodulatory EVs, and responsive-release concepts extrapolated from gland biology or other diseases; no disease-specific validation is claimed here.	Candidate targets (proposed): epithelial–immune crosstalk; B-/T-cell niches; gland inflammatory signals.	Potential objectives (not demonstrated outcomes): reduce gland inflammation and preserve or recover secretory function.	Evidence gap: proposed designs require disease-specific biodistribution, secretion and gland-function assays, and local safety testing before efficacy can be inferred.
Idiopathic inflammatory myopathies (IIM)	Subtype-specific immune dysregulation; myofiber injury; interferon signatures; muscle inflammation and damage	PROPOSED/NOT ESTABLISHED IN IIM: muscle-directed nanocarriers, nucleic-acid delivery and local anti-inflammatory concepts motivated by myositis biology; no disease-specific experimental efficacy is cited for these proposals.	Candidate targets (proposed): muscle-resident immune cells; myofibers; interferon-related and subtype-specific pathways.	Potential objectives (not demonstrated outcomes): reduce subtype-specific muscle inflammation and improve muscle function.	Evidence gap: proposed designs require myositis subtype stratification, muscle biodistribution and functional endpoints before efficacy can be inferred.

Evidence-status note: “DEMONSTRATED” indicates selected published disease-specific preclinical examples (not clinical efficacy), whereas “PROPOSED” indicates hypothesis-generating designs without disease-specific validation cited in this Review. Targets and potential functions listed for SjD and IIM are research objectives, not demonstrated treatment effects. Abbreviations: EV, extracellular vesicle; FLS, fibroblast-like synoviocyte; IIM, idiopathic inflammatory myopathy; LN, lupus nephritis; LNP, lipid nanoparticle; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain-containing 3; RA, rheumatoid arthritis; ROS, reactive oxygen species; SARDs, systemic autoimmune rheumatic diseases; SjD, Sjögren’s disease; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; Tfh, T follicular helper cell; TGF-β, transforming growth factor beta; TRAF6, tumor necrosis factor receptor-associated factor 6; Treg, regulatory T cell.