Engineered Protein‐Cellulose Composite Hydrogels with Superior Mechanical Performance for Bioadhesion

ABSTRACT Strong underwater‐setting adhesives hold transformative potential for tissue repair, yet achieving a combination of high adhesive strength, toughness, energy dissipation, and biocompatibility remains a critical challenge. To address this, we engineered a protein–cellulose composite hydrogel composed of microbially‐produced hybrid proteins that incorporate silk, amyloid, and mussel foot protein (SAM) domains with polydopamine (PDA)‐functionalized cellulose nanocrystals (CNC PDA ). The PDA coating enables robust interfacial interactions between the CNC nanofillers and the SAM protein matrix, dramatically enhancing mechanical performance. Hydrogels containing 10% CNC PDA achieved a tensile strength of 4.9 ± 0.9 MPa, strain of 770% ± 33%, toughness of 17 MJ/m 3 , and damping energy of 202 ± 35 kJ/m 3 —representing 4.7‐, 2‐, 3.6‐, and ninefold increases, respectively, compared to the unreinforced SAM hydrogel. Pre‐stretching further aligned CNC PDA nanofillers within the matrix, enabling tunable enhancement in tensile modulus and ultimate strength. Critically, the composite hydrogels demonstrated strong adhesion to biological tissues, with adhesive strengths of 0.88 ± 0.25 MPa on porcine skin and 1.1 ± 0.3 MPa on bovine bone, far exceeding clinical thresholds for mechanical‐demanding tissue adhesives, while maintaining biocompatibility. This synergistic integration of programmable protein design and functionalized nanomaterials provides a versatile platform for next‐generation bioadhesives, addressing key unmet needs in bone repair and regenerative medicine.