The clinical success of bioinert, tissue‐interfacing metallic implants is greatly jeopardized by complications such as infections, inflammation, and poor regeneration or biointegration, especially concerning diabetics. Implants featuring self‐renewable surfaces that sequentially dictate antibacterial/anti‐inflammatory, immunomodulatory, and pro‐healing/‐regenerative functionalities represent an emerging solution. Herein, fusing triple marine bioinspirations, namely the multilayered interlocked interfaces of mollusk shells, the adhesive/reactive chemistries of mussels, and the self‐renewing, release‐active mucus layers of corals, a self‐adaptive interfacial engineering strategy that imparts self‐renovating surfaces and temporally‐activatable biofunctionalities to various inert biometallic devices is presented. Specifically, sandwich‐like multilayered coatings are in situ constructed, comprising a substrate‐derived micro/nanostructured prelayer, a mussel‐inspired bioadhesive interlayer, and a polyphenol–antibiotic dynamically‐crosslinked therapeutic gel toplayer. The dynamic bonds within the gel allowed pH/reactive oxygen species‐responsive surface degradation, localized release of multifunctional therapeutics, and conditional exposure of cell‐supportive chemical moieties and micro/nanotopographies. Systematic in‐vitro, in‐ovo, and in‐vivo (spanning osseous, subcutaneous, and wound‐closure implantations) studies demonstrated that the functionalized bone implants or wound closure staples possessed adaptive biocompatibility (cyto‐/hemo/‐tissue‐compatibility) and biofunctionalities to combat device‐associated infections and spur diabetic tissue repair. This study underscores the potential of self‐adaptive coating strategies for orchestrating complex (even contradictory) biological functions in addressing challenging medical conditions that require implant intervention.
