Controlled rapamycin release through microparticles induces autophagy and prevents senescence in chondrocytes under stress.

Current treatments for osteoarthritis (OA) offer symptomatic relief but do not prevent or halt the disease progression. Chronic low‐grade inflammation is considered a significant driver of OA. Specialized proresolution mediators are powerful agents of resolution but have a short in vivo half‐life. In this study, we have engineered a Resolvin D1 (RvD1)‐loaded nanoliposomal formulation (Lipo‐RvD1) that targets and resolves the OA‐associated inflammation. This formulation creates a depot of the RvD1 molecules that allows the controlled release of the molecule for up to 11 days in vitro. In surgically induced mice model of OA, only controlled‐release formulation of Lipo‐RvD1 was able to treat the progressing cartilage damage when administered a month after the surgery, while the free drug was unable to prevent cartilage damage. We found that Lipo‐RvD1 functions by damping the proinflammatory activity of synovial macrophages and recruiting a higher number of M2 macrophages at the site of inflammation. Our Lipo‐RvD1 formulation was able to target and suppress the formation of the osteophytes and showed analgesic effect, thus emphasizing its ability to treat clinical symptoms of OA. Such controlled‐release formulation of RvD1 could represent a patient‐compliant treatment for OA.

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease‐modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Rapamycin‐loaded in poly(lactic‐co‐glycolic acid) microparticles (RMPs) induced autophagy, prevented senescence, and sustained sulphated glycosaminoglycans production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra‐articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery‐induced OA when administered as a prophylactic or therapeutic regimen. Together, the study demonstrates the feasibility of using RMPs as a potential clinically translatable therapy to prevent the progression of post‐traumatic OA.

Osteoarthritis (OA) is the most common joint disorder and currently affects >500 million patients worldwide, with ~60% of them also suffering from obesity. There is no drug approved for human use that changes the course of OA progression. OA is one of the most common comorbidities of obesity, and obesity‐related OA (ObOA) is a serious health concern because it shows heightened severity of tissue damage and also predominantly affects the working population. Unresolved inflammation is a major driver of ObOA, thus, resolving disease‐associated inflammation is a viable strategy to treat ObOA. Resolvins are highly potent molecules that play a role in the resolution of inflammation and promote tissue healing. However, small molecules (like Resolvin D1; RvD1) have to be administered frequently or prior to injury because they lose their in vivo activity rapidly either by lymphatic clearance, or oxidation‐mediated deactivation. In this study, we have encapsulated RvD1 in liposomes and established its efficacy in the mouse model of ObOA at much lower dosages than freely administered RvD1. Liposomal RvD1 (lipo‐RvD1) acted as a source of the RvD1 molecules for ~11 days in vitro in synovial fluid derived from patients. When administered prophylactically or therapeutically, lipo‐RvD1 suppressed cartilage damage in male C57BL/6 mice compared to untreated and free RvD1 treatments. This efficacy was achieved by increasing the proportion of the proresolution M2 macrophages over proinflammatory M1 macrophages in the synovial membrane. These results show the potential of lipo‐RvD1 as an anti‐OA agent.

No abstract