{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:41:53Z","timestamp":1789184513333,"version":"build-2803163510"},"reference-count":227,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["R15GM155803"],"award-info":[{"award-number":["R15GM155803"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biophysica"],"abstract":"<jats:p>The glomerular filtration barrier poses a significant challenge for circulating proteins, with molecules below ~60\u201370 kDa facing rapid renal clearance. Endogenous proteins have evolved sophisticated evasion mechanisms including oligomerization, carrier binding, electrostatic repulsion, and FcRn-mediated recycling. Understanding these natural strategies provides blueprints for engineering therapeutic proteins with improved pharmacokinetics. This review examines how endogenous proteins resist filtration, evaluates their application in protein engineering, and discusses clinical translation including established technologies (PEGylation, Fc-fusion) and emerging strategies (albumin-binding domains, glycoengineering). We address critical challenges of balancing half-life extension with tissue penetration, biological activity, and immunogenicity\u2014essential considerations for the rational design of next-generation therapeutics with optimized dosing and enhanced efficacy.<\/jats:p>","DOI":"10.3390\/biophysica6010004","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:52:57Z","timestamp":1768319577000},"page":"4","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Survival Strategies Against Kidney Filtration: Implications for Therapeutic Protein Engineering"],"prefix":"10.3390","volume":"6","author":[{"given":"William P.","family":"Heaps","sequence":"first","affiliation":[{"name":"Department of Physics and Astronomy, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Elise","family":"Packard","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina M.","family":"McCammon","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6848-4832","authenticated-orcid":false,"given":"Tyler P.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph P.","family":"Talley","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4438-183X","authenticated-orcid":false,"given":"Bradley C.","family":"Bundy","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8884-9724","authenticated-orcid":false,"given":"Dennis","family":"Della Corte","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41392-024-02107-5","article-title":"Advance in peptide-based drug development: Delivery platforms, therapeutics and vaccines","volume":"10","author":"Xiao","year":"2025","journal-title":"Signal Transduct. 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