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.