Precision-targeted nanodelivery systems for intra-articular treatment of knee osteoarthritis: recent breakthroughs and translational challenges.

Knee osteoarthritis (KOA) is a progressive whole-joint disorder characterized by cartilage degeneration, synovial inflammation, subchondral bone remodeling, and pathological alterations of the intra-articular (IA) microenvironment. Conventional IA therapies-including corticosteroids, hyaluronic acid, and emerging biologics-provide only transient relief due to rapid synovial clearance, poor cartilage penetration, and limited targeting specificity. Recent advances in nanotechnology have enabled the development of precision-targeted IA nanodelivery systems capable of overcoming anatomical, biomechanical, and biochemical barriers inherent to the osteoarthritic joint. This review summarizes recent breakthroughs in the rational engineering of nanocarriers, including optimization of physicochemical parameters, cartilage- and cell-specific targeting ligands, microenvironment-responsive release mechanisms, lubricating and mechanically adaptive nanomaterials, and integrated theranostic platforms. Progress in preclinical rodent and large-animal models is evaluated, alongside emerging translational evidence and early clinical experience. Remaining challenges-including long-term biocompatibility, pharmacokinetic heterogeneity across OA phenotypes, scalable manufacturing, and regulatory classification-are critically discussed. We highlight future directions centered on personalized nanotherapy, artificial intelligence-assisted carrier design, human-relevant joint organoids, and phenotype-stratified clinical trials. Collectively, precision-targeted IA nanodelivery represents a promising frontier toward clinically viable disease-modifying osteoarthritis drugs (DMOADs) and may ultimately shift KOA treatment from symptomatic management to true disease modification.