Bioprinted dECM particles-laden microgels enhance the mesenchymal stromal cell paracrine effect for myocardial infarction treatment

Despite guideline-directed reperfusion and pharmacological therapies, myocardial infarction (MI) continues to pose substantial clinical challenges, with high incidence and mortality rates. Mesenchymal stromal cell (MSC) transplantation represents a promising therapeutic strategy, yet its efficacy remains limited by poor survival and unstable paracrine function of transplanted cells within the hostile infarct microenvironment. Here, we developed an integrated microcarrier system via digital light processing, which encapsulates MSCs within microgels functionalized with cardiac-derived decellularized extracellular matrix (dECM) particles (termed MSCs@dECMMG). By leveraging the native biochemical composition and structural cues of cardiac dECM, this bioinspired microcarrier was designed not only to enhance MSC viability but also to actively modulate their secretory activity. Conditioned medium from MSCs@dECMMG promoted angiogenic responses in human umbilical vein endothelial cells and attenuated oxidative stress‑induced Apoptosis in H9c2 cells. In the rat MI model, local implantation of MSCs@dECMMG markedly improved the left ventricular ejection fraction from 32.03% to 60.77%, reduced the fibrotic area by 17.44%, and increased the left ventricular wall thickness by 2.6-fold. Collectively, this study demonstrates that a dECM‑integrated microgel can serve as a bioactive carrier that directs MSC secretory signaling, offering a novel strategy to advance cell‑based therapy for MI. STATEMENT OF SIGNIFICANCE: Low survival and unstable paracrine effects of transplanted MSCs in the hostile infarct microenvironment remain a major clinical challenge. Addressing how to specifically enhance MSC paracrine function is critical for effective cardiac repair. Here, we present a precision-engineered microcarrier system that integrates mechanically ground cardiac dECM particles into DLP-bioprinted microgels to deliver MSCs. Unlike prior studies focusing on proliferation or differentiation behaviors, we further uncovered and harnessed cardiac dECM to potentiate MSC paracrine signaling, markedly improving myocardial repair following MI. This introduces a new dimension to dECM application-from guiding differentiation to paracrine enhancement-while providing a translational-ready platform with scalability and controllability for future cell-based therapies.