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However, their therapeutic potential remains limited by their rapid renal clearance. In this study, anti\u2010HER2 Nb\u2010loaded liposomes with dual functionalization combining polyethylene glycol 2000 (PEG) and cyclic cell\u2010penetrating peptides are developed to ameliorate their pharmacokinetic behavior while retaining binding specificity. Liposomal formulations with high encapsulation efficiencies are produced with dual centrifugation. Biophysical characterization reveals that PEGylation effectively mitigates cCPP\u2010induced membrane destabilization, ensuring structural integrity. In vitro assays confirm that, despite the steric shielding by PEG, the encapsulated Nbs retain their functionality and specific binding to HER2\u2010overexpressing cells. In vivo studies in zebrafish larvae demonstrate excellent biocompatibility and lack of immunogenicity. Crucially, liposomal encapsulation significantly modulates the pharmacokinetic profile of Nbs in rats, reducing renal accumulation compared to free Nbs. This study presents a robust liposomal platform that successfully balances the stealth properties of PEG with the functional benefits of cCPPs. Consequently, this platform offers an effective strategy to enhance the therapeutic window of low\u2010molecular\u2010weight biologics.<\/jats:p>","DOI":"10.1002\/advs.75646","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:57:21Z","timestamp":1778533041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Balancing Stealth and Targetability: cCPP\u2010 and PEG\u2010Modified Liposomes for the Targeted Delivery of Anti\u2010HER2 Nanobodies"],"prefix":"10.1002","volume":"13","author":[{"given":"Giulia","family":"Pander","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Technology Institute of Pharmacy and Molecular Biotechnology Heidelberg University Heidelberg Germany"},{"name":"Department of Nuclear Medicine Heidelberg University Hospital Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria del 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