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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 serious CVDs. With the progression of MI, glutathione amounts in heart tissues increase. MiR‐499 (for the inhibition of cardiomyocyte apoptosis) and plasmid encoding vascular endothelial growth factor (for the promotion of angiogenesis) are sequentially delivered for systemic treatment of MI. Such treatment produces impressive results in restoring heart function and suppressing cardiac hypertrophy. Due to the wide existence of redox agents in cells, the proposed unlockable delivery nanovehicle and staged therapy strategy can provide new methods to effectively treat different serious diseases.
Unlockable core–shell nanocomplexes with self‐accelerating nucleic acid release are structurally designed as a novel type of delivery vehicle. The newly designed unlockable vector is successfully utilized for effective miRNA–pDNA staged gene therapy of serious cardiovascular diseases.