Delivery of potential natural disease-modifying osteoarthritis drugs: Beyond polyphenols and flavonoids

Osteoarthritis (OA) is a whole-joint disorder in which cartilage, synovium, subchondral bone, meniscus, and the infrapatellar fat pad deteriorate under chronic inflammatory and mechanical stress. To date, no disease-modifying osteoarthritis drug (DMOAD) has reached approval, largely due to single-pathway targeting, insufficient joint-specific exposure, and heterogeneous OA phenotypes. Polyphenols and flavonoids are well-known natural compounds and have been extensively studied for their potential applications in OA and drug delivery. This review looks beyond commonly known polyphenols and flavonoids to profile underexplored natural chemotypes with intrinsically multi-node biology and credible potential for intra-articular (IA) translation: alkaloids, phytosteroids/withanolides, phytosterols, rare triterpenoids, marine sulfated polysaccharides, polynucleotides, humic/fulvic (including Shilajit-derived) fractions, and plant-derived oligosaccharides. For each class, this review summarizes mechanisms (anti-inflammatory, anti-catabolic, pro-anabolic, anti-angiogenic, and redox/mitochondrial) and OA-relevant evidence across pre-clinical and clinical models. Connections are then drawn between pharmacology and delivery science, including IA depots (PLGA microspheres), shear-thinning or in-situ gelling hydrogels, and advanced options such as lipidic/polymeric nanocarriers, cartilage-binding motifs, and stimuli-responsive linkers (e.g., ROS/MMP-cleavable), alongside distilling practical design rules: particle size for joint retention, charge/affinity for cartilage penetration, and compartment-aware targeting of synovium versus osteochondral interfaces. Collectively, engineered joint exposure paired with multi-node natural pharmacology offers a plausible route to first-in-class natural DMOADs.