Human　heavy-chain　ferritin　(HFn)　possesses　a　stable　and　uniform　cage-like　structure,　tumor-targeting　properties,　self-assembly　capabilities,　and　biocompatibility,　rendering　it　an　ideal　candidate　for　drug　delivery.　Here,　we　developed　a　dual　modified　HFn-based　nanocage　(DFn)　that　targets　the　urokinase-type　plasminogen　activator　receptor　(uPAR)　and,　at　the　same　time,　is　responsive　to　the　tumor　microenvironment　for　controlled　extracellular　drug　release.　This　DFn　was　used　to　co-encapsulate　a　photosensitizer　(CPZ)　and　a　hypoxia-activated　prodrug　(TPZ),　creating　the　multifunctional　nanoparticles　C/T@DFn.　In　vitro　cellular　assays　demonstrated　that　C/T@DFn　significantly　outperformed　both　unmodified　HFn-based　nanoparticles　and　its　counterpart　without　the　uPAR-targeting　motif　in　inhibiting　tumor　cell　survival,　proliferation,　and　migration,　and　showed　enhanced　tumor　cell　spheroids　penetration.　In　vivo　studies　further　demonstrated　the　improved　tumor-specific　accumulation　and　antitumor　efficacy　of　the　loaded　cargo　in　the　DFn　nanocages　in　comparison　with　wild-type　HFn.　This　improved　therapeutic　effect　is　achieved　through　receptor-mediated　targeting　and　tumor　microenvironment-responsive　release　of　the　cargo　from　the　DFn　nanocages,　resulting　in　synergistic　action　of　CPZ　and　TPZ　within　the　tumor　tissue.　Overall,　this　study　introduces　an　ideal　ferritin-based　nanoplatform　for　the　efficient　co-delivery　of　therapeutic　agents,　offering　a　promising　strategy　for　targeted　tumor　therapy.　©　2025　Elsevier　B.V.