Abstract: Injectable hydrogels hold significant promise for cell therapy; however, their clinical translation is often hindered by insufficient mechanical strength and undesirable foreign body responses (FBR) in vivo. Inspired by the reinforcement mechanism of styrene-butadiene-styrene (SBS) elastomers, we propose a cell-mediated covalent crosslinking strategy for constructing a hybrid injectable hydrogel system. This hydrogel is formed via in situ reaction between primary amine groups on the surface of islet-like MIN6 cell aggregates and amino groups on a well-hydrated copolypeptide, mediated by a bifunctional crosslinker, bis-N-hydroxysuccinimide polyethylene glycol (NHS-PEG-NHS). By mimicking the polystyrene aggregation domain anchoring observed in SBS elastomers, the incorporation of cell-mediated crosslinking points not only enabled gentle in situ encapsulation of viable cell clusters, but also significantly enhanced the hydrogel's compressive modulus and swelling resistance. The copolypeptide is synthesized via ring-opening polymerization of L-serine, D-serine, and L-lysine, initiated by lithium hexamethyldisilazide. The resulting polymer features a hydrophilic, non-fouling backbone enriched with amide and hydroxyl groups, providing a strong “dual hydrogen-bond hydration” effect. This structure imparts excellent biocompatibility and antifouling properties, minimizing immune cell recruitment at the host-material interface, thereby supporting the long-term viability of encapsulated cells. In vivo subcutaneous implantation in C57BL/6 mice reveals that the peptide-based hydrogels induce only mild inflammatory responses, as evidenced by low pro-inflammatory cytokine expression, reduced macrophage accumulation, and minimal collagen capsule formation. These results demonstrate that the proposed cell-mediated crosslinked hydrogel offers a versatile platform combining injectability, mechanical robustness, cytocompatibility, and immunomodulatory capacity for effective cell encapsulation and delivery in biomedical applications such as islet transplantation and cell-based therapies.