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.