The in vivo results showed that the optimized LSB in situ forming hydrogel (LSB4c) has superiority over the optimized LOR-loaded bilosome (LB4) and the free drug hydrogel in the management of inflammation and osteoarthritis with a significant elevation in OPG level and reduction in RANKL, MAPK, and ERK1 levels as well as significant enhancement in the histopathological evaluation of the knee joint. The gene discussed is TNFRSF11B; the disease is osteoarthritis.