Prolonged cell persistence with enhanced multipotency and rapid angiogenesis of hypoxia pre-conditioned stem cells encapsulated in marine-inspired adhesive and immiscible liquid micro-droplets

Stem cell therapies are emerging regenerative treatments for ischemic and chronic diseases. Although high cell retention and prompt angiogenesis are prerequisites to improving efficacy, advancements have not yet been developed. Here, we proposed long-term surviving and angiogenesis-inducing stem cell with high cell retention thanks to fluid immiscible liquid micro-droplets bio-inspired by a glue modality ‘complex coacervate’ found in the sandcastle worm. Formed by the Coulombic force between polycationic MAP and polyanionic hyaluronic acid, the exploited coacervate micro-droplets enabled the encapsulation of stem cells. The underwater adhesiveness facilitated integrating the encapsulated stem cells onto various surfaces with impressive cell retention after facile injection. Stem cells encapsulated in the coacervate platform formed cell clusters capable of pre-adjusting to hypoxia by expressing hypoxia-inducible factor 1α (HIF-1α), increasing viability and reducing apoptosis under hypoxia and ischemia as well as normoxia. Interestingly, multipotent and angiogenic factors were significantly enhanced by HIF-1α expression. In the in vivo evaluation, the coacervate platform showed impressive angiogenesis with biocompatibility and long-term cell retention capacity with sustainable release as protein factories. Therefore, the proposed MAP-based water-immiscible, injectable, sticky, and bioactive 3D coacervate micro-droplets offers a promising tool for chronic diseases in body fluid-rich environments. High cell retention, long-term survival, and rapid angiogenesis are prerequisites of successful stem cell therapy. However, no previous advancements have simultaneously satisfied all of these requirements. In this work, we clearly developed a novel, revolutionary stem cell carrier platform with underwater adhesiveness from a mussel-derived glue protein and water immiscibility from a sandcastle-worm-inspired glue modality via ‘complex coacervation’. To the best of our knowledge, no report has emerged employing coacervate as a stem cell therapeutic platform. This fluid-immiscible, injectable, sticky, and bioactive 3-dimensional stem cell micro-droplets demonstrated the excellent stem cell retention and viability under hypoxia environments and enhanced multipotent and angiogenic effects with minimal immune response.