Biomaterials as kinetic translators of microbial metabolite signaling in cardiovascular disease

Microbial metabolites, particularly short-chain fatty acids (SCFAs), play critical roles in regulating endothelial, immunometabolic, and mitochondrial pathways central to cardiovascular homeostasis. Despite strong mechanistic relevance, their translation into therapeutic interventions has remained limited. This failure does not arise from insufficient biological potency. Instead, it reflects a fundamental pharmacokinetic mismatch between the transient, spatially constrained nature of metabolite signaling and the systemic, poorly controlled exposure profiles imposed by conventional delivery strategies. In this review, we propose that biomaterials can function as kinetic translators, converting inherently unstable microbial metabolites into programmable cardiovascular signals by actively shaping their spatiotemporal presentation. Rather than functioning as passive carriers, these biomaterial systems exhibit intrinsic responsiveness. This property enables controlled modulation of metabolite release through material degradation, stimulus-dependent behavior, localized pulse delivery, and microenvironment-triggered activation. We integrate current knowledge of microbial metabolite signaling with principles of smart material design to identify key pharmacokinetic failure points that limit therapeutic efficacy. A decision-oriented synthesis framework is presented to align specific kinetic mismatches with corresponding biomaterial strategies, prioritizing material selection based on functional control of exposure rather than formulation complexity. Finally, translational challenges including incomplete PK/PD models, limited large-animal validation, and regulatory considerations for metabolite-material combination products are discussed. Overall, this review reframes biomaterial-assisted microbial metabolite delivery as a signaling-centric, smart therapeutic strategy, offering a conceptual roadmap for advancing programmable cardiovascular interventions. • Microbial metabolites modulate cardiovascular GPCR and epigenetic signaling. • Free metabolite PK limits stability, bioavailability, and sustained exposure. • Nano-enabled biomaterials stabilize SCFAs and provide controlled local delivery. • Targeted, responsive carriers enhance endothelial and immunometabolic regulation. • Linking biomaterial design to metabolite PK drives translational CVD therapies.