Marine-inspired proteinaceous coacervates as an injectable extracellular matrix mimicry for enhanced stem cell delivery

Injectable stem cell therapy offers advantages, including minimally invasive administration and expedited recovery. However, clinical translation remains limited due to substantial loss of injected cells—up to 90% within hours post-injection—from mechanical stress, hostile microenvironments, and insufficient extracellular matrix (ECM) interactions. Here, we propose a bioengineered mussel-inspired coacervate system that reconstitutes the protective ECM microenvironment for enhanced injectable stem cell delivery. This platform utilizes a fusion protein incorporating the integrin-binding Arg-Gly-Asp (RGD) motif into proximal thread matrix protein (PTMP), sharing structural homology with von Willebrand factor type A (vWF-A) domains. The resulting coacervate, CoPTMP-RGD, formed via electrostatic complexation with hyaluronic acid (HA), exhibits shear-thinning injectability, hemocompatibility, and efficient cell encapsulation. In vitro , PTMP-RGD improves mesenchymal stem cell (MSC) adhesion, proliferation, and multilineage differentiation while preserving stemness. In vivo , CoPTMP-RGD enhances cell retention and promotes neovascularization. These findings position CoPTMP-RGD as a robust injectable platform addressing key bottlenecks in stem cell therapy.