---
OA_place: publisher
OA_type: hybrid
_id: '22959'
abstract:
- lang: eng
  text: 'With this status report, we aim to provide a timely snapshot of the protein
    engineering field as a broad and rapidly advancing discipline that integrates
    computational, molecular biology, structure-guided, evolutionary, and synthetic
    approaches to create new and improved proteins with tailored structures and useful
    functions. The report is organized into eight thematic areas spanning core methodologies
    and major application domains, including enzymes, therapeutics, detection, synthetic
    biology, and materials. Contributions from experts across these areas highlight
    both the historical foundations and recent advances in their respective fields,
    with particular emphasis on the growing influence of machine learning and artificial
    intelligence-based methods. Emerging from this broad overview is a central message:
    protein engineering appears to be entering a golden age, defined by a rapidly
    accelerating pace of progress, even as significant challenges in design, screening,
    and real-world application remain. Looking ahead, the continued integration of
    computational and experimental strategies is poised to further accelerate the
    impact of protein engineering across an expanding range of economically and societally
    important sectors, from therapeutics and molecular imaging to diagnostics, plastic
    recycling, and industrial chemistry.'
acknowledgement: "Research in the lab of H.A. is supported by the National Institutes
  of Health (R01EB033172, R01EB035430, and R01AG077773).\r\n\r\nResearch in the lab
  of F.H.A. is supported by the US Army Research Office cooperative agreement for
  the Institute for Collaborative Biotechnologies (W911NF-19-2-0026) and the US Department
  of Energy, Office of Science, Office of Basic Energy Sciences (DE-SC0021141). This
  report was prepared as an account of work sponsored by an agency of the US Government.
  Neither the US Government nor any agency thereof, nor any of their employees, makes
  any warranty, express or implied, or assumes any legal liability or responsibility
  for the accuracy, completeness, or usefulness of any information, apparatus, product,
  or process disclosed, or represents that its use would not infringe privately owned
  rights. Reference herein to any specific commercial product, process, or service
  by trade name, trademark, manufacturer, or otherwise does not necessarily constitute
  or imply its endorsement, recommendation, or favoring by the US Government or any
  agency thereof. The views and opinions of authors expressed herein do not necessarily
  state or reflect those of the US Government or any agency thereof.\r\n\r\nResearch
  in the lab of D.B. has been supported by National Institutes of Health (NIH) (R35-GM158123-01
  and R01-GM068462).\r\n\r\nResearch in the lab of H.B. is supported by grants from
  the Bill & Melinda Gates Foundation and Oxford Nanopore Technologies.\r\n\r\nResearch
  in the lab of R.E.C. is supported by grants from the Japan Society for the Promotion
  of Science (JSPS) (23K26794, 24H00489, and 24H02267), Japan Science and Technology
  Agency (JST) (JPMJCR25T3), the Mitsubishi Foundation, and the NIH (U01NS123658).\r\n\r\nResearch
  in the lab of P.C. is supported by grants from the Vidyasirimedhi Institute of Science
  and Technology (VISTEC), NSRF via the Program Management Unit for Human Resources
  & Institutional Development (PMU-B) Research and Innovation grant number B05F640089,
  and KasikornBank Public Company Limited.\r\n\r\nResearch in the lab of R.A.C. is
  supported by grants from the Natural Sciences and Engineering Research Council of
  Canada (RGPIN-2021-03484, RGPAS-2021-00017, and ALLRP-597074-24), the Human Frontier
  Science Program (RGP0004/2022) and the Canada Foundation for Innovation (26503 and
  42695). B.J.S. was supported by an NSERC Canada Graduate Research Scholarship.\r\n\r\nResearch
  in the lab of V.G.H.E. is supported by grants from the European Research Council,
  ERC (grant number 856446, CUBE), the Novo Nordisk Foundation (Emerging Investigator
  grant to A.V.; grant number 0061165) and the Research Council of Norway (grant numbers
  309558, Centre for Industrial Biotechnology, SFI-IB, and 257622, Bio4Fuels).\r\n\r\nThis
  project in the lab of R.F. was supported by Robert A. Welch Foundation (AT-0051-20221212),
  and the Cancer Prevention and Research Institute of Texas (grant RR230018).\r\n\r\nResearch
  in the lab of M.S.F. is supported by ETH Zurich and the Swiss National Science Foundation
  (SNSF) under grant number CR00I5-235927.\r\n\r\nThis project in the lab of J.J.G
  is supported by the NIH (R35 GM141881) and a National Science Foundation (NSF) Graduate
  Research Fellowship Program to M.C.\r\n\r\nRelated research in the lab of B.H. is
  supported by the German Research Foundation (DFG) Project Number 391977956—SFB 1357
  Microplastics, subproject C03 and by the European Union’s Horizon 2020 research
  and innovation programme under grant agreement No 951375 (ERC Synergy—ArtMotor).\r\n\r\nRelated
  work in the lab of S.C.L.K. is supported by the NSF under Grant No. 2414074. S.C.L.K.
  is the Georgia Research Alliance—Vasser Wooley Chair of Molecular Design at Georgia
  Tech.\r\n\r\nResearch in the lab of N.K. is supported by grants from the JSPS (24H02261).\r\n\r\nThis
  project in the lab of B.K. was supported by the NIH (R35 GM131923).\r\n\r\nResearch
  in the lab of R.E.K. on bispecific antibodies is supported by a grant from the Baden-Württemberg
  Stiftung and various industry collaborations. Past research was funded by the Deutsche
  Krebshilfe, the BMBF, and the Deutsche Forschungsgemeinschaft.\r\n\r\nResearch in
  the lab of R.D.L. (Protein Engineering and Structural Genomics group) is supported
  by grants from Brazilian National Research Council—CNPq (303833/2022-0, 307370/2025-9),
  the Oswaldo Cruz Fondation—Fiocruz (VPPIS-004-FIO-22, IAM-005-FIO-22, VPPCB-002-FIO25),
  and the Brazilian National Supercomputing Center—LNCC.\r\n\r\nChemical protein synthesis
  research in the lab of L.L. is supported by NSFC (22137005, 22227810, T2488301)
  and New Cornerstone Science Foundation.\r\n\r\nResearch in the lab of M.M.M. is
  supported by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship (202250/Z/16/Z);
  the Biotechnology and Biological Sciences Research Council (BB/W015730/1) and a
  UKRI Postdoc Guarantee Fellowship (Horizon Europe Guarantee via EPSRC EP/Z000823/1
  to L.F.G).\r\n\r\nResearch in the lab of F.Z. is partially supported by the Natural
  Science Foundation of Shaanxi Province (2025SF-YBXM-421).\r\n\r\nResearch in the
  lab of J.K.N. is supported by the NIH (R35GM155044), Biohub, San Francisco, the
  Pew Charitable Trusts, The Vallee Foundation, The Shurl and Kay Curci Foundation,
  the Bakar Fellows Program, and a Sloan Research Fellowship. I.J.O. acknowledges
  support from a Gilliam Fellowship from the Howard Hughes Medical Institute.\r\n\r\nResearch
  in the lab of J.N.P. is supported by the Natural Science and Engineering Research
  Council of Canada (RGPIN-N-2018-04686) and the Canada Research Chair in Engineering
  of Applied Proteins (CRC-2020-00171). D.J.F. is supported by a fellowship from the
  Fonds de recherche du Québec.\r\n\r\nResearch in the lab of A.P. has been supported
  predominantly by grants from the SNSF, the European Union, the European Research
  Council, as well as by pre- and postdoctoral fellowships to the co-workers.\r\n\r\nResearch
  in the lab of Y.Q. is supported by a Horizon Europe Guarantee ERC Starting Grant
  (EP/Z000351/1) and a Biotechnology and Biological Sciences Research Council Research
  Grant (BB/W00349X/1).\r\n\r\nJ.C.R. acknowledges partial support from the SNSF Postdoc.Mobility
  (P500PN_214290). The author thanks Chenghao Liu and Jason Yang for fruitful discussions.\r\n\r\nResearch
  in the lab of S.S. is supported by a NWO-VIDI grant from the Netherlands Organization
  for Scientific Research (NWO, VI.Vidi.213.025) and the European Research Council,
  ERC (grant agreement number 101075934, ReCNNSTRCT).\r\n\r\nResearch in the lab of
  J.B.S. is supported by a Helmsley Charitable Trust grant and a Swim Across America
  grant.\r\n\r\nThis project in the lab of C.L.T. was supported by a grant from the
  National Institute of General Medical Sciences of the NIH (R35GM136367).\r\n\r\nResearch
  on ncAAs in the lab of J.A.V. is supported by a grant from the National Institute
  of General Medical Sciences of the NIH (R35GM133471) and a grant from the NSF (2339201).
  The content is solely the responsibility of the author and does not necessarily
  represent the official views of the NIH or the NSF.\r\n\r\nResearch in the lab of
  A.M.W is supported by an NIH Director’s New Innovator Award (DP2GM149548), a David
  and Lucille Packard Fellowship for Science and Engineering (2021-73007), an Ono
  Pharma Foundation Breakthrough Science Initiative Award (149802896), and the University
  of Wisconsin—Madison Department of Biochemistry.\r\n\r\nProjects in the lab of A.H-W.Y.
  are supported by NIH/NIBIB R00EB031913, UCSC startup/Innovation Catalyst Grant,
  and Chan Zuckerberg Initiative (2024-337820).\r\n\r\nResearch in the lab of J.Zhang
  is supported by NIH grants R35 CA197622, R01 DK073368, R01 DE030497, R01 HL162302,
  R01 CA262815, and RF1 MH126707.\r\n\r\nResearch in the lab of H. Z. is supported
  by the DOE Center for Advanced Bioenergy and Bioproducts Innovation (U.S. Department
  of Energy, Office of Science, Biological and Environmental Research Program under
  Award Number DE-SC0018420), National Science Foundation (NSF) (DBI-2400058, OISE-2435374,
  IIS-2435755, and CHE-2505932), and National Institutes of Health (NIH) (AI144967).
  Any opinions, findings, and conclusions or recommendations expressed in this material
  are those of the author(s) and do not necessarily reflect the views of the DOE,
  NSF or NIH.\r\n\r\nThe authors are grateful to the anonymous peer reviewers and
  to Anna Devor for inspiration and guidance for preparing this manuscript."
article_number: gzag020
article_processing_charge: No
article_type: review
author:
- first_name: Hui-wang
  full_name: Ai, Hui-wang
  last_name: Ai
- first_name: Frances H
  full_name: Arnold, Frances H
  last_name: Arnold
- first_name: Doug
  full_name: Barrick, Doug
  last_name: Barrick
- first_name: Hagan
  full_name: Bayley, Hagan
  last_name: Bayley
- first_name: Alfie-Louise R
  full_name: Brownless, Alfie-Louise R
  last_name: Brownless
- first_name: Robert E
  full_name: Campbell, Robert E
  last_name: Campbell
- first_name: Roger
  full_name: Castells-Graells, Roger
  last_name: Castells-Graells
- first_name: Pimchai
  full_name: Chaiyen, Pimchai
  last_name: Chaiyen
- first_name: Roberto A
  full_name: Chica, Roberto A
  last_name: Chica
- first_name: Lauren O
  full_name: Chisholm, Lauren O
  last_name: Chisholm
- first_name: Daniel
  full_name: Christ, Daniel
  last_name: Christ
- first_name: Guo-Chao
  full_name: Chu, Guo-Chao
  last_name: Chu
- first_name: Michael
  full_name: Chungyoun, Michael
  last_name: Chungyoun
- first_name: Vincent G H
  full_name: Eijsink, Vincent G H
  last_name: Eijsink
- first_name: Michael B
  full_name: Elowitz, Michael B
  last_name: Elowitz
- first_name: Douglas J
  full_name: Fansher, Douglas J
  last_name: Fansher
- first_name: Rudi
  full_name: Fasan, Rudi
  last_name: Fasan
- first_name: Gabriel
  full_name: Foley, Gabriel
  last_name: Foley
- first_name: Michelle S
  full_name: Frei, Michelle S
  last_name: Frei
- first_name: Andreas
  full_name: Gagsteiger, Andreas
  last_name: Gagsteiger
- first_name: Ruiyan
  full_name: Gao, Ruiyan
  last_name: Gao
- first_name: Elizabeth M J
  full_name: Gillam, Elizabeth M J
  last_name: Gillam
- first_name: Jeffrey J
  full_name: Gray, Jeffrey J
  last_name: Gray
- first_name: Luis F
  full_name: Guerra, Luis F
  last_name: Guerra
- first_name: Birte
  full_name: Höcker, Birte
  last_name: Höcker
- first_name: Zhiyang
  full_name: Jin, Zhiyang
  last_name: Jin
- first_name: Shina Caroline Lynn
  full_name: Kamerlin, Shina Caroline Lynn
  last_name: Kamerlin
- first_name: Nobuyasu
  full_name: Koga, Nobuyasu
  last_name: Koga
- first_name: Roland E
  full_name: Kontermann, Roland E
  last_name: Kontermann
- first_name: Brian
  full_name: Kuhlman, Brian
  last_name: Kuhlman
- first_name: Olivia A
  full_name: Langlois, Olivia A
  last_name: Langlois
- first_name: Dongyang
  full_name: Li, Dongyang
  last_name: Li
- first_name: Roberto D
  full_name: Lins, Roberto D
  last_name: Lins
- first_name: Chang C
  full_name: Liu, Chang C
  last_name: Liu
- first_name: Lei
  full_name: Liu, Lei
  last_name: Liu
- first_name: Diego
  full_name: López Barreiro, Diego
  last_name: López Barreiro
- first_name: Peilong
  full_name: Lu, Peilong
  last_name: Lu
- first_name: Sohum
  full_name: Mehta, Sohum
  last_name: Mehta
- first_name: Ikumi
  full_name: Miyazaki, Ikumi
  last_name: Miyazaki
- first_name: Manuel M
  full_name: Müller, Manuel M
  last_name: Müller
- first_name: Serge
  full_name: Muyldermans, Serge
  last_name: Muyldermans
- first_name: Naoto
  full_name: Nemoto, Naoto
  last_name: Nemoto
- first_name: Jeff
  full_name: Nivala, Jeff
  last_name: Nivala
- first_name: James K
  full_name: Nuñez, James K
  last_name: Nuñez
- first_name: Izaiah J
  full_name: Ornelas, Izaiah J
  last_name: Ornelas
- first_name: Joelle N
  full_name: Pelletier, Joelle N
  last_name: Pelletier
- first_name: Andreas
  full_name: Plückthun, Andreas
  last_name: Plückthun
- first_name: Owen T
  full_name: Porth, Owen T
  last_name: Porth
- first_name: Kridsadakorn
  full_name: Prakinee, Kridsadakorn
  last_name: Prakinee
- first_name: Yujia
  full_name: Qing, Yujia
  last_name: Qing
- first_name: Julia
  full_name: Reisenbauer, Julia
  id: 51d862e9-36ee-11f0-86d3-8534c85a5496
  last_name: Reisenbauer
- first_name: Sandy
  full_name: Schmidt, Sandy
  last_name: Schmidt
- first_name: Oliver
  full_name: Seifert, Oliver
  last_name: Seifert
- first_name: Mikhail G
  full_name: Shapiro, Mikhail G
  last_name: Shapiro
- first_name: Rachna
  full_name: Sharma, Rachna
  last_name: Sharma
- first_name: Nilmani
  full_name: Singh, Nilmani
  last_name: Singh
- first_name: Benjamin J
  full_name: Smith, Benjamin J
  last_name: Smith
- first_name: Jamie B
  full_name: Spangler, Jamie B
  last_name: Spangler
- first_name: Rie
  full_name: Tatsumi-Koga, Rie
  last_name: Tatsumi-Koga
- first_name: Takuya
  full_name: Terai, Takuya
  last_name: Terai
- first_name: Henrik
  full_name: Terholsen, Henrik
  last_name: Terholsen
- first_name: Mattias
  full_name: Tolhurst, Mattias
  last_name: Tolhurst
- first_name: Katherine W
  full_name: Tripp, Katherine W
  last_name: Tripp
- first_name: Vanessa Tanja
  full_name: Trossmann, Vanessa Tanja
  last_name: Trossmann
- first_name: Chandra L
  full_name: Tucker, Chandra L
  last_name: Tucker
- first_name: Onur
  full_name: Turak, Onur
  last_name: Turak
- first_name: James A
  full_name: Van Deventer, James A
  last_name: Van Deventer
- first_name: Anikó
  full_name: Várnai, Anikó
  last_name: Várnai
- first_name: Isabelle F T
  full_name: Viana, Isabelle F T
  last_name: Viana
- first_name: Amy M
  full_name: Weeks, Amy M
  last_name: Weeks
- first_name: K Dane
  full_name: Wittrup, K Dane
  last_name: Wittrup
- first_name: Kingsley L-J
  full_name: Wong, Kingsley L-J
  last_name: Wong
- first_name: Chenggang
  full_name: Xi, Chenggang
  last_name: Xi
- first_name: Todd O
  full_name: Yeates, Todd O
  last_name: Yeates
- first_name: Andy Hsien-Wei
  full_name: Yeh, Andy Hsien-Wei
  last_name: Yeh
- first_name: Jin
  full_name: Zhang, Jin
  last_name: Zhang
- first_name: Tiger S
  full_name: Zhang, Tiger S
  last_name: Zhang
- first_name: Huimin
  full_name: Zhao, Huimin
  last_name: Zhao
- first_name: Fang
  full_name: Zheng, Fang
  last_name: Zheng
- first_name: Jingyi
  full_name: Zhu, Jingyi
  last_name: Zhu
- first_name: Sacha
  full_name: Zinn, Sacha
  last_name: Zinn
citation:
  ama: 'Ai H, Arnold FH, Barrick D, et al. Protein engineering: Status report. <i>Protein
    Engineering, Design and Selection</i>. 2026;39. doi:<a href="https://doi.org/10.1093/protein/gzag020">10.1093/protein/gzag020</a>'
  apa: 'Ai, H., Arnold, F. H., Barrick, D., Bayley, H., Brownless, A.-L. R., Campbell,
    R. E., … Zinn, S. (2026). Protein engineering: Status report. <i>Protein Engineering,
    Design and Selection</i>. Oxford University Press. <a href="https://doi.org/10.1093/protein/gzag020">https://doi.org/10.1093/protein/gzag020</a>'
  chicago: 'Ai, Hui-wang, Frances H Arnold, Doug Barrick, Hagan Bayley, Alfie-Louise
    R Brownless, Robert E Campbell, Roger Castells-Graells, et al. “Protein Engineering:
    Status Report.” <i>Protein Engineering, Design and Selection</i>. Oxford University
    Press, 2026. <a href="https://doi.org/10.1093/protein/gzag020">https://doi.org/10.1093/protein/gzag020</a>.'
  ieee: 'H. Ai <i>et al.</i>, “Protein engineering: Status report,” <i>Protein Engineering,
    Design and Selection</i>, vol. 39. Oxford University Press, 2026.'
  ista: 'Ai H, Arnold FH, Barrick D, Bayley H, Brownless A-LR, Campbell RE, Castells-Graells
    R, Chaiyen P, Chica RA, Chisholm LO, Christ D, Chu G-C, Chungyoun M, Eijsink VGH,
    Elowitz MB, Fansher DJ, Fasan R, Foley G, Frei MS, Gagsteiger A, Gao R, Gillam
    EMJ, Gray JJ, Guerra LF, Höcker B, Jin Z, Kamerlin SCL, Koga N, Kontermann RE,
    Kuhlman B, Langlois OA, Li D, Lins RD, Liu CC, Liu L, López Barreiro D, Lu P,
    Mehta S, Miyazaki I, Müller MM, Muyldermans S, Nemoto N, Nivala J, Nuñez JK, Ornelas
    IJ, Pelletier JN, Plückthun A, Porth OT, Prakinee K, Qing Y, Reisenbauer J, Schmidt
    S, Seifert O, Shapiro MG, Sharma R, Singh N, Smith BJ, Spangler JB, Tatsumi-Koga
    R, Terai T, Terholsen H, Tolhurst M, Tripp KW, Trossmann VT, Tucker CL, Turak
    O, Van Deventer JA, Várnai A, Viana IFT, Weeks AM, Wittrup KD, Wong KL-J, Xi C,
    Yeates TO, Yeh AH-W, Zhang J, Zhang TS, Zhao H, Zheng F, Zhu J, Zinn S. 2026.
    Protein engineering: Status report. Protein Engineering, Design and Selection.
    39, gzag020.'
  mla: 'Ai, Hui-wang, et al. “Protein Engineering: Status Report.” <i>Protein Engineering,
    Design and Selection</i>, vol. 39, gzag020, Oxford University Press, 2026, doi:<a
    href="https://doi.org/10.1093/protein/gzag020">10.1093/protein/gzag020</a>.'
  short: H. Ai, F.H. Arnold, D. Barrick, H. Bayley, A.-L.R. Brownless, R.E. Campbell,
    R. Castells-Graells, P. Chaiyen, R.A. Chica, L.O. Chisholm, D. Christ, G.-C. Chu,
    M. Chungyoun, V.G.H. Eijsink, M.B. Elowitz, D.J. Fansher, R. Fasan, G. Foley,
    M.S. Frei, A. Gagsteiger, R. Gao, E.M.J. Gillam, J.J. Gray, L.F. Guerra, B. Höcker,
    Z. Jin, S.C.L. Kamerlin, N. Koga, R.E. Kontermann, B. Kuhlman, O.A. Langlois,
    D. Li, R.D. Lins, C.C. Liu, L. Liu, D. López Barreiro, P. Lu, S. Mehta, I. Miyazaki,
    M.M. Müller, S. Muyldermans, N. Nemoto, J. Nivala, J.K. Nuñez, I.J. Ornelas, J.N.
    Pelletier, A. Plückthun, O.T. Porth, K. Prakinee, Y. Qing, J. Reisenbauer, S.
    Schmidt, O. Seifert, M.G. Shapiro, R. Sharma, N. Singh, B.J. Smith, J.B. Spangler,
    R. Tatsumi-Koga, T. Terai, H. Terholsen, M. Tolhurst, K.W. Tripp, V.T. Trossmann,
    C.L. Tucker, O. Turak, J.A. Van Deventer, A. Várnai, I.F.T. Viana, A.M. Weeks,
    K.D. Wittrup, K.L.-J. Wong, C. Xi, T.O. Yeates, A.H.-W. Yeh, J. Zhang, T.S. Zhang,
    H. Zhao, F. Zheng, J. Zhu, S. Zinn, Protein Engineering, Design and Selection
    39 (2026).
das_tickbox: '1'
dataavailabilitystatement: No new data were generated or analysed in support of this
  research.
date_created: 2026-09-17T11:06:36Z
date_published: 2026-07-17T00:00:00Z
date_updated: 2026-10-01T09:29:15Z
day: '17'
ddc:
- '570'
department:
- _id: JuRe
doi: 10.1093/protein/gzag020
external_id:
  pmid:
  - '42466865'
file:
- access_level: open_access
  checksum: 4015ecfe11b3b0cac757d5bdd10d3c1d
  content_type: application/pdf
  creator: dernst
  date_created: 2026-10-01T09:24:22Z
  date_updated: 2026-10-01T09:24:22Z
  file_id: '23019'
  file_name: 2026_ProteinEngineeringDesignSelection_Ai.pdf
  file_size: 12603911
  relation: main_file
  success: 1
file_date_updated: 2026-10-01T09:24:22Z
fulldoi: https://doi.org/10.1093/protein/gzag020
has_accepted_license: '1'
intvolume: '        39'
language:
- iso: eng
month: '07'
oa: 1
oa_version: Published Version
pmid: 1
publication: Protein Engineering, Design and Selection
publication_identifier:
  eissn:
  - 1741-0134
  issn:
  - 1741-0126
publication_status: published
publisher: Oxford University Press
quality_controlled: '1'
researchdata_availability: no
scopus_import: '1'
status: public
supplementarymaterial: no
title: 'Protein engineering: Status report'
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 39
year: '2026'
...