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Nanoparticles-based drug delivery systems show great promise for cancer therapy due to the advantages of crossing physiological barrier, high drug availability and good stability. However, deep tumor penetration, long blood circulation, and rapid drug release remain intractable problems for nanocarriers. In this work, we report a tumor microenvironment-sensitive nanodrug delivery system containing both acidic pH and hypoxia response sites to achieve enhanced drug permeability and on-demand release for precise cancer therapy. The covalent organic frameworks (COFs) with introduced azobenzene (azo) groups were used as employed as nanocarrier, and modified by pH-sensitive sulfamide-based zwitterionic polymers (PBA), followed by loading with the chemotherapeutic drug doxorubicin (DOX) to obtain COF-PBA@DOX. Copolymer PBA achieved charge conversions in tumor acidic environment, resulting in a positive charge on the nanocarrier surfaces, thus facilitating the augmented tumor accumulation. Meanwhile, azo which was formed the COF carrier, could be reduced to amines by the highly expressed azoreductase under tumor hypoxia conditions, resulting in nanoparticle dissociation and the drug-controlled release at the solid tumor sites. The fabricated dual-responsive nanomedicine, based on the surface charge-reversal of zwitterion in the acidic environment of tumor, can realize the accumulation and targeted drug release at the tumor site, which has great potential as a nanocarrier in tumor therapy. [Display omitted] [ABSTRACT FROM AUTHOR]