Photodynamic　therapy　(PDT)　is　a　promising　cancer　treatment　modality　with　advantages　of　minimal　in-vasiveness,　repeatable　therapy,　and　mild　systemic　toxicity.　However,　the　limited　bioavailability　of　photo　-sensitizer　(PS),　tumor　hypoxia,　and　the　presence　of　antiapoptotic　proteins　in　cancer　cells,　has　hampered　the　efficiency　of　PDT.　To　address　these　limitations,　herein,　we　developed　a　hyaluronic　acid　(HA)　based　nanosystem　(HA-Ce6-Hemin@DNA-Protamine　NPs,　HCH@DP)　loaded　with　chlorin　e6　(Ce6,　as　PS),　hemin　(as　mimetic　catalase)　and　antisense　oligonucleotide　(ASO)　of　B-cell　lymphoma　2　(Bcl-2)　anti-apoptosis　protein　via　a　simple　electrostatic　self-assembly　method　for　enhanced　PDT　of　hypoxic　solid　tumors.　The　HCH@DP　can　target　deliver　the　PS　and　ASO　to　tumor　cells　via　cancer　cell　overexpressed　HA　receptors　(i.e.,　CD44　or　RHAMM).　The　Ce6　was　released　from　HA-ss-Ce6　(HSC　conjugates)　after　the　reaction　of　cleavable　disulfide　bond　with　glutathione　(GSH),　which　recovered　the　fluorescence　and　phototoxicity　of　Ce6　upon　laser　irradiation.　Meanwhile,　the　catalase-mimicking　hemin　(degradation　of　HA-eda-hemin　by　hyaluronidase)　decomposed　the　tumor　overdressed　endogenous　H2O2　to　oxygen,　which　relieved　tumor　hypoxia　and　further　overcome　hypoxia-associated　resistance　of　PDT.　Furthermore,　the　inhibition　of　Bcl-2　expression　by　Bcl-2　ASO　also　greatly　improved　the　cellular　sensitivity　to　PDT.　Both　in　vitro　and　in　vivo　results　showed　the　tumor　cell　targeting　ability,　hypoxia　relief　and　significantly　enhanced　antitumor　PDT　efficacy　of　HCH@DP　for　hypoxic　tumor　cells　upon　laser　irradiation.　Thus,　by　improving　the　target　delivery　of　PS　and　ASO,　relieving　tumor　hypoxia,　and　down-regulation　of　anti-apoptotic　proteins,　this　HCH@DP　nanosystem　achieved　enhanced　PDT　efficiency　against　hypoxic　tumors.　In　general,　our　work　provided　a　promising　strategy　to　increase　the　utilization　of　key　components　(PS　and　oxygen)　of　PDT　and　the　cell　sensitivity　to　PDT　by　targeting　co-delivery　PS　and　oligonucleotides　to　tumor　cells　via　a　biocompatible　HA　based　carrier,　thereby　achieving　efficiently　PDT　treatment　of　hypoxic　solid　tumors　with　potential　transla-tion　possibility.Statement　of　significance　The　efficiency　of　PDT　against　solid　tumor　is　severely　restricted　by　the　limited　bioavailability　of　photo　-sensitizer,　tumor　hypoxia,　and　the　presence　of　antiapoptotic　proteins　in　cancer　cells.　Herein,　we　have　developed　an　activatable　hyaluronic　acid　(HA)　based　nanosystem　(HA-Ce6-Hemin@DNA-Protamine　NPs,　HCH@DP)　via　a　simple　electrostatic　self-assembly　method　for　PDT　treatment　of　hypoxic　solid　tumors.　The　HCH@DP　enabled　to　target　co-delivery　of　photosensitizer　and　antisense　oligonucleotide　to　tumor　cells,　overcoming　tumor　hypoxia　through　in　situ　oxygen　production　and　improving　cellular　sensitivity　by　efficiently　reducing　anti-apoptosis　effect　of　cancer　cells　for　synergistically　enhancing　PDT　efficiency.　This　work　suggests　a　promising　strategy　to　develop　small　molecule　drug　and　oligonucleotides　co-delivery　nanoplatforms　for　efficiently　PDT　treatment　of　hypoxic　solid　tumor.　(c)　2022　Acta　Materialia　Inc.　Published　by　Elsevier　Ltd.　All　rights　reserved.