ABSTRACT Wounds, surgical or trauma in origin, is a major healthcare burden when it persists. One of the common complications of non-healing chronic diabetic (D) wounds is stalled inflammation. Mechanisms regulating such derailed immune response is therefore of extraordinary interest. This proposal rests on our novel observation that keratinocytes (K) of the wound-edge tissue cross-talk with visiting macrophages via K-originating exosomes which carry genetic information to macrophages (immune cells) in a highly organized and directed manner. Exosomes may be viewed as biology nanocarriers, released by live cells, and have been implicated in numerous inflammatory conditions including sepsis. Exomotif in genes select them for exosomal packaging. We propose that miR-21 is one such non-coding gene the precursor of which, pre- miR-21, is packaged in K-originating exosomes and delivered to wound macrophages to resolve inflammation in a timely manner. This process of cross-talk is compromised in D. We observed that surface protein chemistry of exosomes, i.e. presence of mannose, targets it for delivery to wound macrophages. D modifies this surface protein chemistry resulting in mannose modifications which compromises uptake of these exosomes by wound macrophages. To add clinical significance to the proposed work we seek to study exosome surface mannose modifications in poorly controlled, well controlled D compared to non-D patients with chronic wounds. The following three specific aims are thus proposed: Aim 1: Determine whether K- macrophage cross-talk is compromised in D wound-edge tissue. 1.1 Uptake of K-originating exosomes by wound-site macrophages (wmφ) is compromised under conditions of D. 1.2 Compromised K-macrophage cross-talk in D wound causes impairment in resolution of inflammation. Aim 2: Test whether surface glycoproteins of K-derived exosomes from the wound-site are glycosylated under conditions of D impairing macrophage targeting. 2.1 Wound- edge K-derived exosomes (κ-GFPEXO) undergoes mannose isomerization under conditions of D. 2.2 Mannose on the surface of κ-GFPEXO at the wound-site is glycated under conditions of D such that macrophage targeting is impaired. Aim 3: Isolate exosomes from D and non-D human chronic wound fluid to characterize exosomal subsets and their surface mannose modifications. This proposal from an early stage investigator is aimed at laying the foundation of a laboratory that would be dedicated to the study of exosomal mechanisms in surgical and traumatic injury and repair. Such efforts are likely to contribute to seminal advances in our understanding of wound repair and inform novel therapies.