Silk Bioconjugates: From Chemistry and Concept to Application

Abstract

Medical silks have captured global interest. While silk sutures have a long track record in humans, silk bioconjugates are still in preclinical development. This perspective examines key advances in silk bioconjugation, including the fabrication of silk-protein conjugates, bioconjugated silk particles, and bioconjugated substrates to enhance cell-material interactions in two and three dimensions. Many of these systems rely on chemical modification of the silk biopolymer, often using carbodiimide and reactive ester chemistries. However, recent progress in enzyme-mediated and click chemistries has expanded the molecular toolbox to enable biorthogonal, site-specific conjugation in a single step when combined with recombinant silk fibroin tagged with noncanonical amino acids. This perspective outlines key strategies available for chemical modification, compares the resulting silk conjugates to clinical benchmarks, and outlines open questions and areas that require more work. Overall, this assessment highlights a domain of new sunrise capabilities and development opportunities for silk bioconjugates that may ultimately offer new ways of delivering improved healthcare.

Keywords: bioconjugation; chemistry; polymer therapeutics; silk fibroin; spidroin.

Figure 1

Schematic representations and the reactive amino acid composition of (a) Bombyx mori silk fibroin, (b) Antheraea mylitta silk fibroin, and (c) native and recombinant spidroins. The scale bars are 0.5 cm in length. The structural composition and reactive amino acid content of silk fibroin have been assembled from refs (, −42).

Figure 2

Popular bioconjugation techniques which display a range of chemoselectivities and utilize the reactive silk fibroin natural amino acid chemistry. The reaction schemes have been adapted from refs ( and −53).

Figure 3

Bioconjugation techniques which display low chemoselectivity and utilize the reactive silk fibroin natural amino acid chemistry. The reaction schemes have been adapted from refs (, , , and −74).

Figure 4

Enzyme-mediated bioconjugation techniques which display site-specificity and utilize the silk fibroin natural amino acids. The reaction schemes have been adapted from refs ( and 78).

Figure 5

Bioconjugation of recombinant silk fibroin using bioorthogonal thiol–maleimide, thiol–ene, and azide–alkyne click chemistry. Reaction schemes have been adapted from refs ( and −120).

Figure 6

(a) Selected considerations for the bioconjugation of silk fibroin using homogeneous and heterogeneous reactions and (b) selected advantages and disadvantages of the bioconjugation techniques discussed herein.