Short-chain fatty acids (SCFAs) such as butyrate are powerful immunomodulators, but their therapeutic translation is severely limited by volatility, rapid metabolism, and poor bioavailability, rendering most conventional polymeric delivery systems ineffective at achieving sustained, biologically relevant exposure. Here, we introduce silk fibroin (SF) as a high-payload, morphology-tunable carrier for volatile metabolites and demonstrate its ability to overcome some of these limitations. Leveraging silk's unique combination of aqueous processability, structural stability, and controllable degradation, we fabricated butyrate-loaded nanoparticles and porous sponges with independently tunable loading and release profiles spanning multiple days. While all formats enabled sustained Fickian release, biological efficacy was strongly form-factor dependent. Critically, nanoparticle-mediated delivery, rather than total butyrate dose, was required to reprogram inflammatory macrophages, driving a pronounced increase in anti-inflammatory IL-10 and promoting M1-to-M2 polarization, whereas diffusely releasing sponge formats were ineffective. These findings establish that material morphology, not release rate alone, governs the immunological outcome of SCFA delivery. More broadly, this work positions silk fibroin as a generalizable platform for the delivery of volatile and rapidly metabolized endogenous metabolites, enabling new therapeutic strategies in immunomodulation and metabolic medicine.
Morton et al. (2026) studied this question.