Oral Administration of <i>Bombyx mori</i> Silk Fibroin Nanoparticles Modulates the Gut Microbiota in Healthy Mice

Silk fibroin nanoparticles (SFNPs) have shown great promise as oral drug delivery carriers due to their favorable biocompatibility and tunable release properties. However, their effects on the gut microbiota under physiological conditions remain poorly understood. Herein, we systematically investigated the impact of orally administered SFNPs on the composition and temporal dynamics of the gut microbiome in healthy mice. SFNPs were thoroughly characterized, showing stability in intestinal fluid and structural transition to β-sheet conformation. Our results revealed that SFNP administration induced significant, dose-dependent shifts in microbial communities, notably increasing the Firmicutes/Bacteroidota ratio and enriching potentially beneficial genera such as Faecalibaculum and Dubosiella, while reducing taxa associated with inflammation and metabolic disorders. Medium doses (2.4 and 12 mg/kg) promoted sustained potentially beneficial effects, whereas a high dose (60 mg/kg) led to transient dysbiosis and enrichment of the inflammation-related genus Enterorhabdus. These findings underscore the dose-responsive modulatory effects of SFNPs on gut microbiota and highlight the importance of microecological safety in the design of nanocarrier systems for oral administration. This study provides critical insights into the gut-nanoparticle interface and supports the potential of SFNPs in microbiome-based therapeutics.