Introduction

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by the deterioration of articular cartilage, alterations in subchondral bone, joint pain, and reduced mobility [1,2]. Its global impact is profound: as of 2020, approximately 595 million individuals (≈7.6 % of the global population) were affected by OA, with the prevalence increasing by approximately 132 % since 1990 [1]. Conventional treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injections, and ultimately joint replacement, primarily focus on alleviating symptoms rather than altering fundamental disease progression [2]. Consequently, long-term, non-surgical disease modification remains elusive for the vast majority of patients.

Mesenchymal stem cell (MSC) therapy has emerged as a promising regenerative strategy; however, extracellular vesicles (EVs) derived from MSCs are now recognized as a superior, cell-free alternative [3]. MSC-EVs retain the beneficial paracrine effects of their parent cells, delivering chondroprotective microRNAs, lipids, and growth factors while circumventing the risks of cellular senescence, immune rejection, and tumorigenesis [3,4]. While preliminary preclinical models indicate that MSC-EVs effectively mitigate cartilage degradation and suppress inflammatory mediators, their translation into clinical therapeutics is severely bottlenecked by a lack of fundamental pharmacokinetic (PK) and pharmacodynamic (PD) understanding [5]. Currently, EV therapies suffer from heterogeneous isolation methods that lead to variable intra-articular retention times, erratic biodistribution, and unstandardized clearance rates [5,6].

To successfully transition MSC-EVs into disease-modifying biologic agents, their dosing regimens, which are currently arbitrarily defined across the literature by either bulk protein concentration or particle count, must be systematically evaluated [6]. This meta-analysis not only synthesizes the structural efficacy of MSC-EVs in osteoarthritis models but also critically assesses the preclinical landscape through a translational pharmacological lens. By rigorously quantifying effect sizes and evaluating reporting quality against MISEV 2023 standards [7], we aim to highlight critical gaps in dose-exposure relationships, administration frequency, and EV characterization, thereby establishing a benchmark for ADMET (absorption, distribution, metabolism, excretion, and toxicity)-compliant EV therapeutic development.