Nanobiomaterials for osteoarthritis therapy: Current strategies and future perspectives

Osteoarthritis (OA) is being increasingly recognized as a complex whole-joint disease, yet clinical management remains restricted to symptomatic relief due to the absence of effective disease-modifying OA drugs and the intrinsic limitations of the use of articular cartilage for self-repair. To address the pharmacokinetic challenges of rapid intra-articular clearance and poor tissue penetration, the rapid evolution of nanotechnology has offered innovative paradigms. This review systematically analyzes the convergence of engineering design principles for OA therapy with molecular pathology targets, particularly through the lens of precision medicine. We comprehensively categorize state-of-the-art nanoplatforms into five primary classes, namely, inorganic, lipid-based, natural polymer, synthetic polymer, and hybrid nanomaterials, to elucidate how physicochemical properties such as size effect, surface charge, and biochemical modification are tailored to recapitulate the nanotopography of the extracellular matrix. Beyond serving as delivery vehicles, these advanced nanobiomaterials have been evaluated for their potential to function as stimulus response gating mechanisms that trigger payload release in response to pathological microenvironmental cues such as acidic pH, enzymes, and reactive oxygen species. We highlight the ability of these systems to modulate critical therapeutic targets, including mitochondrial dysfunction, ferroptosis, and macrophage polarization, thereby facilitating the transition from a pro-inflammatory M1 phenotype to a regenerative M2 phenotype. Furthermore, the integration of nanocarriers with drugs, stem cells, gene, and immune therapies are discussed as multimodal strategies to restore physiological homeostasis across the synovium-cartilage-bone axis. Finally, we critically assess the key translational challenges and propose that future progress should prioritize biosafety, scalable manufacturing, and the development of intelligent, multifunctional platforms capable of enabling closed-loop dynamic therapy. This review provides a comprehensive framework for the rational design and engineering of nanobiomaterials for OA therapy, which could offer critical strategic guidance for orthopedic surgeons and clinical researchers to advance the development of OA treatments.