Lubricant Strategies in Osteoarthritis Treatment: Transitioning from Natural Lubricants to Drug Delivery Particles with Lubricant Properties

Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degradation, leading to pain and functional impairment. A key contributor to OA progression is the decline in cartilage lubrication. In physiological conditions, synovial fluid (SF) macromolecules like hyaluronic acid (HA), phospholipids, and lubricin play a crucial role in the boundary lubrication of articular cartilage. In early OA, cartilage damage triggers inflammation, altering SF composition and compromising the lubrication layer. This increases friction between mating interfaces, worsening cartilage degradation and local inflammation. Therefore, early-stage restoration of lubrication (by injecting in the joint different classes of compounds and formulations) could alleviate, and potentially reverse, OA progression. In the light of this, a broad variety of lubricants have been investigated for their ability to reduce friction in OA joints and promote cartilage repair in clinical and preclinical studies. This review examines recent advancements in lubricant-based therapy for OA, focusing on natural, bioinspired, and alternative products. Starting from the currently applied therapy, mainly based on natural lubricants as HA, we will present their modified versions, either in hydrogel form or with specific biomimetic moieties with the aim of reducing their clearance from the joint and of enhancing their lubricating properties. Finally, the most advanced and recent formulation, represented by alternative strategies, will be proposed. Particular emphasis will be placed on those ones involving new types of hydrogels, microparticles, nanoparticles, and liposomes, which are currently under investigation in preclinical studies. The potential application of particles and liposomes could foster the transition from natural lubricants to Drug Delivery Systems (DDSs) with lubricant features; transition which could provide more complete OA treatments, by simultaneously providing lubrication replacement and sustained release of different payloads and active agents directly at the joint level. Within each category, we will examine relevant preclinical studies, highlighting challenges and future prospects.