Injectable hydrogels carrying therapeutic factors to modulate the
infarct immune microenvironment show great potential in the treatment of
myocardial infarction (MI). However, conventional
injectable hydrogels release therapeutic factors in an uncontrolled manner, which leads to poor treatment efficacy and acute side effects on normal tissues. In this work, a
matrix metalloproteinase (
MMP)2/9-responsive
hydrogel system (MPGC4) is developed, considering the characteristics of the post-MI microenvironment. MPGC4 consists of tetra-poly(
ethylene glycol) (PEG)
hydrogels and a composite gene nanocarrier (CTL4) that is composed of
carbon dots (CDots) coupled with
interleukin-4 plasmid
DNA via electrostatic interactions. MPGC4 can be automatically triggered to release CTL4 on demand after MI to regulate the
infarct immune microenvironment. In addition, due to the photoluminescence properties of CDots, a large amount of viscoelastic MPGC4 is found to be retained in situ after injection into the
infarct region without leakage. The in vitro results demonstrate that CTL4 promotes proinflammatory M1 macrophage polarization to the anti-inflammatory M2 subtype and contributes to cardiomyocyte survival through macrophage transition. In a rat model of MI, MPGC4 clears
MMPs and precisely targets CTL4 to the infarcted region. In particular, MPGC4 improves cardiac function by modulating macrophage transition to reduce early inflammatory responses and proangiogenic activity.