Nanomaterials targeting ferroptosis for osteoarthritis treatment: a systematic review of preclinical evidence

Osteoarthritis (OA) lacks effective disease-modifying therapies. Ferroptosis, an iron-dependent form of programmed cell death, has emerged as a novel pathogenic mechanism in OA. Nanomaterials (NMs), with tunable physicochemical properties and targeting capacity, offer promising opportunities for ferroptosis modulation. This systematic review synthesizes preclinical evidence on NM-based strategies in OA.

This review followed PRISMA 2020 guidelines and was prospectively registered on INPLASY (INPLASY202570110). Comprehensive searches of seven databases (PubMed, Embase, Web of Science, Scopus, ProQuest, Ovid, Cochrane Library) were performed up to July 27, 2025. Eligible studies included in vitro and/or in vivo investigations of NM-based approaches targeting ferroptosis in OA models. Independent screening, data extraction, and risk of bias assessment were conducted. Owing to substantial heterogeneity in nanomaterial platforms, experimental models, and outcome measures, a qualitative evidence synthesis was performed and meta-analysis was not considered appropriate.

Twenty-two eligible studies were identified. Investigated nanoplatforms included polymeric nanoparticles, metal-based carriers, nanozymes, hydrogels, and biomimetic systems. Across in vitro and in vivo models, NMs were reported to modulate ferroptosis through regulation of iron metabolism, scavenging of reactive oxygen species, reinforcement of antioxidant defenses, and modulation of ferroptosis-related signaling. Reported preclinical outcomes included attenuation of lipid peroxidation, preservation of mitochondrial integrity, reduction of chondrocyte death, and improvement in cartilage structure and joint function.

Preclinical evidence supports NM-based ferroptosis modulation as a promising avenue for disease-modifying OA therapy. Translation will require standardized protocols, independent replication across diverse settings, adoption of advanced human-relevant models, and integration with multi-target strategies beyond ferroptosis.