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Silk fibroin has the merits of biocompatibility, biodegradability, ease of processing, and feasibility of modification, which present it as a promising drug delivery material. This review focuses on the structures of silk fibroin, the controlled transformation of secondary structures, and the formation mechanism of silk fibroin-based nanoparticles (SFNPs). We also discuss the intrinsic multi-responsive, surface functionalization, and transgenic modification of SFNPs for drug delivery.Chemical computing is something we use every day (e