Macrophage Membrane-Camouflaged Nanozyme Microneedles Restore Immunovascular Homeostasis Through SPP1-ApoE Signaling in Diabetic Wounds.

Abstract

Chronic diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and disrupted intercellular communication, including altered macrophage-endothelial interactions. In this study, we develop macrophage membrane-camouflaged, didymin (DM)-loaded metal-organic framework microneedles (Mac@DM-MOF MNs), a biomimetic nanozyme platform designed to selectively restore this intercellular communication and re-establish a pro-regenerative microenvironment. RNA-seq and mechanistic analyses identify activation of the SPP1-ApoE signaling axis, an unrecognized pathway linking M2 polarization to endothelial activation, as a central mechanism by which Mac@DM-MOF MNs synchronize inflammation resolution and angiogenesis. Nanozyme-mediated ROS scavenging relieves redox stress, while DM promotes macrophage polarizationtoward the reparative M2 state. M2-derived SPP1 subsequently interacts with endothelial ApoE, thereby promoting endothelial sprouting, and restoring vascular functionality. In diabetic mouse and Bama mini pig models, Mac@DM-MOF MNs attenuate inflammation, rescue angiogenic deficits, and markedly accelerate wound closure. Importantly, vascular restoration further reinforces M2 polarization, forming a self-sustaining pro-healing feedback loop. Our findings define macrophage-endothelial coupling as a pivotal regulatory mechanism in diabetic wound repair and introduce a synergistic nanomedicine-based strategy that concurrently resolves chronic inflammation and restores angiogenesis.