Computational design of non-porous pH-responsive antibody nanoparticles

Erin C Yang; Robby Divine; Marcos C Miranda; Andrew J Borst; Will Sheffler; Jason Z Zhang; Justin Decarreau; Amijai Saragovi; Mohamad Abedi; Nicolas Goldbach; Maggie Ahlrichs; Craig Dobbins; Alexis Hand; Suna Cheng; Mila Lamb; Paul M Levine; Sidney Chan; Rebecca Skotheim; Jorge Fallas; George Ueda; Joshua Lubner; Masaharu Somiya; Alena Khmelinskaia; Neil P King; David Baker

doi:10.1038/s41594-024-01288-5

Computational design of non-porous pH-responsive antibody nanoparticles

Nat Struct Mol Biol. 2024 May 9. doi: 10.1038/s41594-024-01288-5. Online ahead of print.

Authors

Erin C Yang^{1

2

3}, Robby Divine^{1

2

4

5}, Marcos C Miranda^{1

6}, Andrew J Borst^{1

2}, Will Sheffler¹, Jason Z Zhang^{1

2}, Justin Decarreau^{1

2}, Amijai Saragovi^{1

2}, Mohamad Abedi^{1

2}, Nicolas Goldbach^{1

7}, Maggie Ahlrichs^{1

2}, Craig Dobbins^{1

2}, Alexis Hand^{1

2}, Suna Cheng^{1

2}, Mila Lamb^{1

2}, Paul M Levine^{1

2}, Sidney Chan^{1

2}, Rebecca Skotheim^{1

2}, Jorge Fallas^{1

2}, George Ueda^{1

2}, Joshua Lubner^{1

2}, Masaharu Somiya^{1

8}, Alena Khmelinskaia^{1

9

10}, Neil P King^{11

12}, David Baker^{13

14

15}

Affiliations

¹ Institute for Protein Design, University of Washington, Seattle, WA, USA.
² Department of Biochemistry, University of Washington, Seattle, WA, USA.
³ Graduate Program in Biological Physics, Structure & Design, University of Washington, Seattle, WA, USA.
⁴ Graduate Program in Biochemistry, University of Washington, Seattle, WA, USA.
⁵ Department of Chemistry, University of California, Davis, Davis, CA, USA.
⁶ Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁷ Technical University of Munich, Munich, Germany.
⁸ SANKEN, Osaka University, Osaka, Japan.
⁹ Transdisciplinary Research Area 'Building Blocks of Matter and Fundamental Interactions (TRA Matter)', University of Bonn, Bonn, Germany.
¹⁰ Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
¹¹ Institute for Protein Design, University of Washington, Seattle, WA, USA. neilking@uw.edu.
¹² Department of Biochemistry, University of Washington, Seattle, WA, USA. neilking@uw.edu.
¹³ Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
¹⁴ Department of Biochemistry, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
¹⁵ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. dabaker@uw.edu.

PMID: 38724718
DOI: 10.1038/s41594-024-01288-5

Abstract

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery.