In Situ Reprogrammings of Splenic CD11b⁺ Cells by Nano‐Hypoxia to Promote Inflamed Damage Site‐Specific Angiogenesis

Abstract

Clinical translation of nanoparticles is limited because of their short circulation time, which hampers targeting to prolong therapeutic effects. Angiogenesis is required to regenerate damaged sites under inflammation, and CD11b+ cells turn vasculogenic under hypoxia. As a turning‐point strategy to increase the circulation time, this study explores liposomal targeting of splenic CD11b+ cells, which are gathered in the spleen and move to inflamed sites inherently. Moreover, nano‐hypoxia is strategized as a therapeutic method by loading liposomes with a hypoxic‐mimetic agent (CoCl2) to induce in situ reprogramming of splenic CD11b+ cells upon venous injection. Consequently, the vasculogenic potential of reprogrammed cells accelerates regeneration through inflammation‐responsive homing. Hydrophilic coating of liposomes improves the selectivity of splenic targeting in contrast to fast targeting without coating. Hypoxia chambers and surgical induction of splenic hypoxia are compared to validate the reprogramming effect. The strategy is validated in mouse models of inflamed skin, ischemic hindlimbs, and 70% hepatectomy compared with a conventional approach using bone marrow cells. Intravital multiphoton microscopy, 19F 2D/3D MRI, and microchannel hydrogel chips for 3D tissue culture are used as advanced tools. Overall, nanocarrier change to CD11b+ cells prolong targeting by inducing in situ reprogramming for inflammation‐responsive vasculogenic therapy.

In situ reprogramming as a pro-angiogenic inducer to rescue ischemic tissues

“…In this review, we examine the research on neovascularization conducted over the past decades and discuss in situ reprogramming as an improvement strategy. We also review recent research strategies that apply in situ reprogramming in neovascularization [31].…”

“…In situ Reprogramming as a Pro-Angiogenic Inducer One research team identified a convergence point by focusing on the spleen to overcome the insufficient dose and complex ex vivo processing issues of EPC therapy while simultaneously addressing the targeting issue of in situ reprogramming [31]. The spleen is an ideal site for in situ reprogramming because it stores a substantial number of monocytes that migrate to areas, such as sites of myocardial infarction, during inflammation [47,48].…”