VEGF Mimetic Peptide-Modified Bifunctional Nanosystem for Targeted Drug Delivery in Myocardial Infarction

<i>Aim</i>: To develop a bioengineered nanomedicine integrating vascular regeneration and nitric oxide modulation for precision therapy of myocardial ischemia/reperfusion (I/R) injury. <i>Materials and Methods</i>: The nanomedicine (A-M@P-Q) was synthesized through mesoporous polydopamine/polydopamine (mPDA/PDA) coordination, functionalized with VEGF receptor (VEGFR)-targeting peptide (QK), and loaded with l-arginine. Therapeutic validation incorporated cellular hypoxia/reoxygenation (H/R) models and murine myocardial ischemia/reperfusion (I/R) studies, supported by in vivo biodistribution tracking and biosafety evaluation. <i>Results</i>: The A-M@P-Q nanomedicine demonstrated dual therapeutic efficacy: QK peptide promoted angiogenesis via VEGFR2 (Kdr) activation, while l-arginine restored NO homeostasis. In vitro studies revealed that both M@P-Q and A-M@P-Q enhanced NO production, downregulated cellular and mitochondrial ROS level, improved mitochondrial function, inhibited cell apoptosis, and promoted angiogenesis in H/R-triggered endothelial cells; however, A-M@P-Q exerted a stronger effect. Short-term in vivo studies found that A-M@P-Q enhanced phosphor-Kdr and NO level, inhibited cell apoptosis, and promoted early angiogenesis in myocardial I/R mice. Biodistribution study confirmed Kdr-targeted accumulation of M@P-Q nanoparticles in the infarcted myocardium. Systemic biocompatibility study showed negligible toxicity of the nanomedicine. <i>Conclusion</i>: This bifunctional nanosystem A-M@P-Q pioneers a coordinated therapeutic paradigm synchronizing neovascularization with NO promotion, establishing a clinically translatable strategy for I/R injury management through targeted myocardial repair.