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Photodynamic therapy (PDT) is a promising cancer therapy due to the evident advantages of a rapid curative effect, minimal or non-invasiveness, and circumvention of drug resistance. However, the hydrophobicity of photosensitizers and the hypoxic tumor microenvironment in solid tumors reduce the therapeutic effect of PDT immensely. Herein, we construct a program-mable hybrid mesoporous silica nanoparticle/DNA nanogel (H-DNA nanogel) for enhanced PDT. The H-DNA nanogel is constituted with a virus-like mesoporous silica nanoparticle (VMSN) as the core to provide an appropriate nano-interface and a self-assembly programmable DNA hydrogel layer based on rolling circle amplification (RCA) as the shell. Two kinds of G-quadruplex structures inserted with a hemin and zinc phthalocyanine (ZnPc) photosensitizer are introduced into the H-DNA nanogel by base pairing. The two modules of G-quadruplex structure work as an oxygen supplement in the hypoxic tumor microenvironment and increase the yield of singlet oxygen, respectively. Our hybrid DNA nanogel system provides a modular platform for efficient cancer PDT and has great potential in the broader biomedical field.