Drug resistance remains a major unresolved challenge in cancer treatment. Here, we introduce a FerroTAC system, a targeted liposome platform co-delivering Oligo-PROTACs and iron nanoparticles to overcome drug resistance. Oligo-PROTACs degrade NRF2, a key transcription factor in drug resistance, while iron nanoparticles trigger ferroptosis to bypass conventional resistance pathways. For efficient tumor delivery, we designed a liposome vehicle functionalized with iRGD peptides and tumor microenvironment-responsive ECM-degrading enzymes. Liposomes modified with iRGD selectively target and penetrate αvβ3/5 integrin-overexpressing cancer cells. Furthermore, collagenases are selectively released via hypoxia-cleavable linkers, effectively degrading ECM barriers and maximizing drug penetration into the tumor. Collectively, FerroTAC provides a multi-mechanism strategy to overcome resistance and enhance anticancer therapeutic efficacy.