Advances in injectable liposome–microspheres platforms for osteoarthritis therapy: from sustained delivery to multifunctional disease modification

Osteoarthritis (OA) is a chronic, whole-joint disorder marked by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, and capsular fibrosis, affecting over 500 million individuals worldwide. Current pharmacotherapies are mainly palliative, with no approved disease-modifying osteoarthritis drugs (DMOADs). Intra-articular (IA) injection provides direct joint access but is hampered by rapid drug clearance and short residence times. Injectable liposome–microsphere (iLMP) systems have recently emerged as integrative delivery platforms that synergistically combine the high loading capacity, targeting versatility, and stimuli-responsiveness of liposomes with the sustained release, lubrication, mechanical support, and protective shielding of hydrogel microspheres. This “nano-in-micro” hierarchical architecture enables prolonged joint retention, spatiotemporally controlled drug release, active cell/tissue targeting, and even gene editing, thereby shifting OA management from symptom alleviation toward true disease modification. In this review, we systematically examine the rational design of iLMPs, covering liposomal composition and functionalization, microsphere fabrication technologies (microfluidics, electrospraying, 3D bioprinting, emulsification), and assembly strategies (embedding, anchoring, adsorption, and matrix hybridization). We then detail their physicochemical determinants—size, surface charge, rheology, and degradation kinetics—and discuss the multifaceted therapeutic mechanisms, including sustained pharmacokinetic modulation, boundary lubrication, active/passive targeting, enzyme/ROS/pH-responsive release, nucleic acid delivery, and exosome-hybrid biofunctionalization. Finally, we critically analyze current translational barriers (scale-up, long-term stability, safety, and cost) and outline future directions toward intelligent, personalized, and combination regimens. With continued advances in biomaterials, microengineering, and precision medicine, iLMPs are poised to become a cornerstone of next-generation OA therapy.