In situ-activated therapy is a decent option for localized diseases with improved efficacies and reduced side effects, which is heavily dependent on the local conversion or activation of bioinert components. In this work, we applied a phospholipid-mimic artemisinin prodrug (ARP) for preparing an injectable nano/microsphere to first realize an in situ-activated therapy of the typical systemically administrated artemisinin-based medicines for a localized rheumatoid arthritis (RA) lesion. ARP is simultaneously an alternative of phospholipids and an enzyme-independent activable prodrug, which can formulate "drug-in-drug" co-delivery liposomes with cargo of partner drugs (e.g., methotrexate). To further stabilize ARP/methotrexate "drug-in-drug" liposomes (MTX/ARPL) for a long-term intra-articular retention, a liposome-embedded hydrogel nano/microsphere (MTX/ARPL@MS) was prepared. After the local injection, the MTX/ARPL could be slowly released because of imine hydrolysis and targeted to RA synovial macrophages and fibroblasts simultaneously. ARP assembly is relatively stable before cellular internalization but disassembled ARP after lysosomal escape and converted into dihydroartemisinin rapidly to realize the effective in situ activation. Taken together, phospholipid-mimic ARP was applied for the firstly localized in situ-activated RA therapy of artemisinin-based drugs, which also provided a brand-new phospholipid-mimic strategy for other systemically administrated prodrugs to realize a remodeling therapeutic schedule for localized diseases.