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Nucleic acid (NA)‐based therapy is proposed to address serious diseases such as cardiovascular diseases (CVDs). Powerful NA delivery vehicles are essential for effective gene therapy. Herein, a novel type of delivery vehicle, an unlockable core–shell nanocomplex (Hep@PGEA) with self‐accelerating NA release, is structurally designed. Hep@PGEA is composed of disulfide‐bridged heparin nanoparticle (HepNP) core and low‐toxicity PGEA cationic shell. In comparison with NA, heparin, a negatively charged polysaccharide macromolecule, exhibits stronger interactions with cationic species. Upon the breakdown of redox‐responsive HepNP cores, unlocked heparin would interact with the outer cationic shells and replace the condensed NA to facilitate NA release. Such unique Hep@PGEA is successfully explored for effective miRNA–pDNA staged gene therapy of myocardial infarction (MI), one of the most …