A quality by design strategy to develop curcumin and siRNA co-loaded lipoplexes to target osteoarthritis-related...

Osteoarthritis (OA) is a prevalent, debilitating disease marked by joint degeneration, pain, and reduced mobility. Among the factors that influence the pathogenesis and progression of OA, oxidative stress and inflammation are of major importance. As curcumin downregulates the expression of many inflammatory cytokines, scavenges free radicals, and upregulates the levels of collagen and aggrecan, it therefore reduces pain and helps with regeneration. On the other hand, oligonucleotides have emerged as next-generation therapeutics, capable of modulating specific gene expression. In this context, delivery of small interfering RNAs (siRNAs) through lipoplexes is a promising approach for repairing damaged cartilage tissues. Our study focused on developing lipoplexes for efficient co-delivery of curcumin and therapeutic siRNA in chondrocytes. In the first step, the Quality-by-design (QbD) principles guided the development of curcumin-loaded cationic liposomes (CLCL) and the selection of the optimum formulation. Further, optimum curcumin-loaded cationic liposomes (Opt-CLCL) were complexed with IL-6 and IL-8 siRNA to form co-loaded lipoplexes. The Opt-CLCL successfully reduced the oxidative stress levels in both patient-derived primary chondrocytes and a human chondrocyte cell line, while co-loaded lipoplexes transfected chondrocytes with no toxicity and efficiently reduced the inflammation markers. Thus, the developed co-loaded lipoplexes are promising for further testing in OA models. Moreover, the optimal vector designed within the study could serve as a platform for incorporating other lipophilic drugs and negatively charged oligonucleotides to address various ailments.