Adhesives have attracted a great deal of attention as an advanced modality in biomedical engineering because of their unique wound management behavior. However, it is a grand challenge for current adhesive systems to achieve robust adhesion due to their tenuous interfacial bonding strength. Moreover, the absence of dynamic adaptability in conventional chemical adhesives restricts neoblasts around the wound from migrating to the site, resulting in an inferior tissue-regeneration effect. Herein, an extracellular matrix-derived biocomposite adhesive with robust adhesion and a real-time skin healing effect is well-engineered. Liquid–liquid phase separation is well-harnessed to drive the assembly of the biocomposite adhesive, with the active involvement of supramolecular interactions between chimeric protein and natural DNA, leading to a robustly reinforced adhesion performance. The bioadhesive exhibits outstanding adhesion and sealing behaviors, with a sheared adhesion strength of approximately 18 MPa, outperforming its reported counterparts. Moreover, the engineered bioderived components endow this adhesive material with biocompatibility and exceptional biological functions including the promotion of cell proliferation and migration, such that the use of this material eventually yields real-time in situ skin regeneration. This work opens up novel avenues for functionalized bioadhesive engineering and biomedical translations.

Melanoma is the most lethal malignancy in skin cancer and may occur at any site and express melanocytes. Due to malignant melanoma's invasion and migration nature, conventional therapies make it challenging to remove the whole tumor tissue while undertaking the high risks of tumor recurrence. Regarding the emerging targeted therapies and immunotherapy, drug resistance and low immunotherapeutic activity remain significant challenges. It is thus becoming urgently important to develop alternative strategies for melanoma therapy. Herein, a novel bifunctional protein-based photothermal bioplaster (PPTB) is developed for non-invasive tumor therapy and skin tissue regeneration. The complexation of adhesive protein and gold nanorods (GNRs) endow the obtained PPTB with good biocompatibility, controllable near-infrared (NIR) light-mediated adhesion performance, and high photothermal performance. Therefore, the PPTB bioagent facilitates skin adhesion and effectively transfers heat from skin to tumor. This behavior endows PPTB capability to eradicate skin tumors conveniently. Thus, the assembly strategy enables this hybrid bioplaster to hold great potential for skin-related tumor treatment.

Naturally inspired proteins are investigated for the development of bioglues that combine adhesion performance and biocompatibility for biomedical applications. However, engineering such adhesives by rational design of the proteins at the molecular level is rarely reported. Herein, it is shown that a new generation of protein-based glues is generated by supramolecular assembly through de novo designed structural proteins in which arginine triggers robust liquid-liquid phase separation. The encoded arginine moieties significantly strengthen multiple molecular interactions in the complex, leading to ultrastrong adhesion on various surfaces, outperforming many chemically reacted and biomimetic glues. Such adhesive materials enable quick visceral hemostasis in 10 s and outstanding tissue regeneration due to their robust adhesion, good biocompatibility, and superior antibacterial capacity. Remarkably, their minimum inhibitory concentrations are orders of magnitude lower than clinical antibiotics. These advances offer insights into molecular engineering of de novo designed protein glues and outline a general strategy to fabricate mechanically strong protein-based materials for surgical applications.

The development of biomedical glues is an important, yet challenging task as seemingly mutually exclusive properties need to be combined in one material, i.e. strong adhesion and adaption to remodeling processes in healing tissue. Here, we report a biocompatible and biodegradable protein-based adhesive with high adhesion strengths. The maximum strength reaches 16.5 ± 2.2 MPa on hard substrates, which is comparable to that of commercial cyanoacrylate superglue and higher than other protein-based adhesives by at least one order of magnitude. Moreover, the strong adhesion on soft tissues qualifies the adhesive as biomedical glue outperforming some commercial products. Robust mechanical properties are realized without covalent bond formation during the adhesion process. A complex consisting of cationic supercharged polypeptides and anionic aromatic surfactants with lysine to surfactant molar ratio of 1:0.9 is driven by multiple supramolecular interactions enabling such strong adhesion. We demonstrate the glue’s robust performance in vitro and in vivo for cosmetic and hemostasis applications and accelerated wound healing by comparison to surgical wound closures.

Adhesive hydrogels have been developed for wound healing applications. However, their adhesive performance is impaired dramatically due to their high swelling on wet tissues. To tackle this challenge, we fabricated a new type of non-swelling protein adhesive for underwater and in vivo applications. In this soft material, the electrostatic complexation between supercharged polypeptides with oppositely charged surfactants containing 3,4-dihydroxylphenylalanine or azobenzene moieties plays an important role for the formation of ultra-strong adhesive coacervates. Remarkably, the adhesion capability is superior to commercial cyanoacrylate when tested in ambient conditions. Moreover, the adhesion is stronger than other reported protein-based adhesives in underwater environment. The ex vivo and in vivo experiments demonstrate the persistent adhesive performance and outstanding behaviors for wound sealing and healing.

Mechanical strong adhesives have been widely explored in many technical fields. Therefore, a great deal of efforts has been devoted to the widespread investigation of synthetic adhesives and bioadhesives. Nevertheless, it is a crucial challenge to produce economical and practical protein-based adhesives with robust adhesion properties for biomedical applications. In this study, the fish swim bladder as raw materials to produce robust adhesives by simple heating-cooling treatment is utilized. The resulting fish swim bladder glue (FSG) reveals excellent lap shear strength on various hard substrates, especially wood and glass, exceeding many commercial available adhesives and artificial protein-based adhesives. In addition, FSG also has low cytotoxicity and minimal inflammatory response, which exhibits considerable adhesion on soft tissues. Notably, the biocompatibility and biodegradability together with robust adhesion performance endow FSG the capacity in accelerating the wound healing and skin regeneration. Overall, these studies provide insight into the protein-based adhesives from natural resources.

Complex coacervation enables important wet adhesion processes in natural and artificial systems. However, existed synthetic coacervate adhesives show limited wet adhesion properties, non-thermoresponsiveness, and inferior biodegradability, greatly hampering their translations. Herein, by harnessing supramolecular assembly and rational protein design, we present a temperature-sensitive wet bioadhesive fabricated through recombinant protein and surfactant. Mechanical performance of the bioglue system is actively tunable with thermal triggers. In cold condition, adhesion strength of the bioadhesive was only about 50 kPa. By increasing temperature, the strength presented up to 600 kPa, which is remarkably stronger than other biological counterparts. This is probably due to the thermally triggered phase transition of the engineered protein and the formation of coacervate, thus leading to the enhanced wet adhesion bonding.

Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.