A hypoxia-sensitive zwitterionic vehicle, D-High-PEI-(A+P), with the ability for antifouling-mediated, stable biotransport and a photodynamic therapy (PDT)-sensitized hypoxic response for spatiotemporal controlled drug release, was developed for the tumor-specific delivery of chemotherapeutics and biomacromolecules. The amphiphilic D-High-PEI-(A+P) was constructed from a betaine monomer (DMAAPS), a photosensitizer (PpIX), and an azobenzene-4,4'-dicarboxylic acid-modified polyethylenimine. Herein paditaxel (PTX) was selected as a common model drug to verify the functions of the designed polymer. First, D-High-PEI-(A+P) was demonstrated to spontaneously coassemble with PTX in aqueous solution with high drug loading (>35%). The desirable antifouling ability of D-High-PEI-(A+P) was independently verified by efficient 4T1 endocytosis in serum alongside systemic tumor targeting. Furthermore, PpIX-mediated PDT was verified to aggravate and homogenize a hypoxic microenvironment at the cell and tissue levels for a sharp responsive disassembly of D-High-PEI-(A+P) and thus a robust drug release in a well-controlled manner. As a result, D-High-PEI-(A+P) amplified the therapeutic outcome of PTX on orthotopic 4T1 mouse models with minimal collateral damage. We proposed that D-High-PEI-(A+P) may serve as a tailor-designed universal vehicle for the tumor-specific delivery of drugs with distinct physicochemical properties.