Natural polysaccharide-nucleic acid nanocomplex alleviates myocardial infarction by driving chronologically programmed macrophage polarization

In the temporal pathological progression of myocardial infarction (MI), acute ischemic injury triggers a macrophage-dominated inflammatory response, where the early M1 phenotype polarization aids in necrotic tissue clearance. However, persistent inflammation drives a pro-fibrotic shift, leading to cardiac remodeling and heart failure, rendering single-target therapies largely ineffective in addressing the full pathological course. To address this challenge, we developed a temporally modulated nanodelivery system. This platform integrates the natural immunomodulator zymosan A (ZymA) with siRNA-21 (SiR21) through intelligent assembly, enabling dual immunoregulatory and gene-silencing functions (ZymA@SiR21). Formulation optimization of ZymA enhanced particle uniformity and surface charge density, improving electrostatic binding with the cationic polymer PDMA for efficient SiR21 loading while boosting biosafety and immune tolerance. The system is associated with the binding of mannose groups on the ZymA surface to mannose receptors to achieve macrophage-specific targeting. This nanoplatform demonstrates time-dependent therapeutic precision: (1) During acute MI, ZymA induces macrophage polarization toward the M1 phenotype, enhancing phagocytic clearance of necrotic debris; (2) In the chronic-phase, released SiR21 sustains macrophage reprogramming to reparative M2 phenotypes and inhibits fibroblast hyperactivation. This "clearance-to-repair" strategy achieved superior outcomes in animal models and no systemic immune hyperactivation. By orchestrating macrophage dynamics, the system accelerates the restoration of inflammation-repair balance post-MI, offering a paradigm-shifting approach for stage-specific cardiac therapy.