Microbiome-Responsive Hydrogels: From Biological Cues to Smart Biomaterials

<b>Background:</b> Stimuli-responsive hydrogels (SRHs) are smart polymeric materials that undergo reversible physicochemical changes in response to abiotic cues and externally applied fields, enabling applications in drug delivery, wound healing, and tissue engineering. However, they exhibit limited biological specificity and do not adequately reflect the dynamic, disease-relevant complexity of native tissue microenvironments. Microbe-colonized tissues display distinctive biochemical features driven, shaped by microbial metabolism, including localized pH gradients, short-chain fatty acid production, secretion of quorum-sensing molecules, biofilm formation, and expression of specialized enzymes. These endogenous, spatiotemporally regulated signals are closely linked to host physiology and pathology but remain underutilized in hydrogel design. This review aims to highlight microbiome-responsive hydrogels (MRHs) as a strategy to address this gap. <b>Methods:</b> This study summarizes current engineering approaches, key microbial stimuli, and emerging biomedical applications of MRHs, with emphasis on translational and regulatory challenges. <b>Results:</b> Microbiome-responsive hydrogels (MRHs) address this gap by leveraging microbial metabolic and biochemical cues to induce swelling, degradation, drug release, antibacterial activity, or structural transformation. By directly coupling to microbe-derived stimuli, MRHs offer improved physiological relevance, enhanced local specificity, and new opportunities for precision therapy targeting disease-associated microbial niches. <b>Conclusions:</b> Despite their promise, MRHs remain an early and fragmented field, lacking standardized biological triggers, material design frameworks, and performance evaluation strategies. This review summarizes current engineering approaches, key microbial stimuli, and emerging biomedical applications, with emphasis on translational and regulatory challenges, positioning MRHs as an underexplored platform for next-generation smart biomaterials.