Photodynamic therapy (PDT) is a promising cancer treatment modality with advantages of minimal invasiveness, repeatable therapy, and mild systemic toxicity. However, the limited bioavailability of photosensitizer (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 HO 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 translation possibility. STATEMENT OF SIGNIFICANCE: The efficiency of PDT against solid tumor is severely restricted by the limited bioavailability of photosensitizer, 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.