Year: 2026
Type: preprint
Abstract: Protein capsids perform a broad range of biological functions 1–4 and can be engineered 5 as delivery vehicles, 6 nanoreactors, 7 biosensors, 8 and vaccines. 9 However, because the protein building blocks that make up these capsids must be expressed in biological systems, their composition is largely restricted to the canonical amino acids, limiting functionality. Assembling capsids from chemically synthesized proteins could circumvent this limitation but has not been accomplished due to a combination of technical challenges. Here we demonstrate the complete chemical synthesis of the 14.1-kDa coat protein of bacteriophage Qβ and its assembly into 180-subunit 2.5-MDa capsids. We exploit the expanded chemical palette afforded by total synthesis to produce mirror-image capsids composed entirely of unnatural D-amino acids. We determine the structures of the L- and D-capsids to 3-Å resolution by cryo-EM and verify their stereochemistry by cryo-ET. D-capsids elicit antibody titers 100-fold lower than their L-counterparts in mice, with the D-capsid response dominated by IgM antibodies. We demonstrate functional delivery in vivo using synthetic L-and D-capsids loaded with luciferase-encoding mRNA. By combining biological self-assembly with chemical synthesis, our results establish a route to producing a new class of programmable nanomaterials for diverse applications.
Source: ChemRxiv
Authors: Alexander Harjung, Chih-Chin Chi, Chuxuan Ling, Mariusz Matyszewski, Nino Makasarashvili, Lisa Kain, Kenna Nagy, Rui Huang, Matthew Campbell, Suyeong Han, Kira Podolsky, Inga Kuschnerus, Stormi Chadwick, Ember M. Tota, Payton Jensen, Moira A. McMahon, David J. Ecker, Luc Teyton, Rees F. Garmann, Neal K. Devaraj
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: National Science Foundation, San Diego State University, Ionis Pharmaceuticals, University of California, San Diego, Advanced Research Projects Agency, Materials Research Science and Engineering Center, Harvard University, Division of Materials Research, Materials Research Science and Engineering Center, University of California, San Diego
OpenAlex ID: W7213917454