Smart nanomaterial-crosslinked hydrogels for biomedical applications

Hydrogels have advanced significantly in biomedical applications, yet their inherent hydrophilic matrices often hinder the efficient encapsulation and controlled release of hydrophobic drugs. Nanomaterial-crosslinked (NMC) hydrogels, in which nanomaterials (NMs) serve as crosslinkers rather than mere fillers, represent an innovative platform. NMC hydrogels synergistically integrate the tissue-mimetic and injectable properties of hydrogels with the versatile functionalities of NMs. This review systematically categorizes and discusses the diverse NM-polymer interactions, including irreversible covalent bonds, dynamic covalent bonds, and non-covalent interactions. These interactions that govern the formation and performance of NMC hydrogels and endow them with unique smart behaviors, such as stimuli-responsive phase transitions, programmable cargo release, self-healing capability, and suitability for 3D/4D bioprinting. Particular emphasis is placed on the design principles of NM-polymer interactions and their role in enhancing mechanical robustness, dynamic adaptability, and biomedical functionality. This review aims to inspire the development of more sophisticated and adaptable NMC hydrogel systems, thereby accelerating their translation into clinical practice. • Elucidates NM-polymer interactions and design blueprints for NM-crosslinked hydrogels, establishing functional ​material frameworks. • Analyzes synergistic hydrogel traits: NM-enhanced mechanics, multi-cargo co-delivery, and coordinated stimulus-response. • Highlights applications from targeted therapy to 4D bioprinting, with translational challenges and prospects.