Hybrid hydrogels for biomedical applications: Addressing challenges in drug delivery through advanced crosslinking and nanocarrier integration

Recent years have witnessed significant advancements in the engineering potential and biomedical applications of hydrogels, driven by improvements in drug discovery, chemical engineering, and biological sciences. These developments have broadened one's knowledge in the selection of polymeric materials from the plethora of natural and synthetic polymers determined by the physicochemical properties of drug substances and their interaction with biological targets. Several attempts have been made to fine-tune the mechanical properties and drug release characteristics of hydrogels using conventional physical crosslinking or chemical crosslinking methods, such as conjugation of polymers, the addition of small crosslinker molecules among polymers, and functionalization of nanocarriers with certain molecules/functional groups for their interaction with polymers. Collectively, this has resulted in facile preparation, localized administration, biocompatibility, target specificity, and controlled release of drugs from hydrogels. Nevertheless, only a limited number of hydrogel systems have progressed to clinical trials and regulatory approval, primarily due to persistent challenges associated with lipophilic drug loading, formulation stability, stimuli responsiveness, and controlled release of pharmaceutical actives. In this review, we address these limitations by critically examining emerging physical and chemical crosslinking strategies, nanocarrier-assisted loading of lipophilic and hydrophilic drugs, and the underlying design principles for fabricating multifunctional hybrid hydrogels. We further evaluate recent advances in the incorporation of diverse nanocarriers, such as polymeric nanoparticles (NPs), metallic NPs, carbon-based NPs, lipid-based nanocarriers, dendrimers, and nanoemulsions into hydrogel matrices, with emphasis on drug release mechanisms and biomedical applications. Finally, the hybrid hydrogels that have advanced to clinical evaluation are highlighted, together with their current clinical status. Overall, this review provides a systematic overview of the recent progress in hybrid hydrogels for controlled drug delivery, while proposing strategic solutions to address key translational challenges.