{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T11:31:05Z","timestamp":1786966265787,"version":"build-2736575974"},"reference-count":77,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The development of theranostic tools for the early detection and localization of tumors represents a major challenge in oncology. Among emerging strategies, the targeting of Programmed Death Ligand-1 (PD-L1), a key immune checkpoint protein overexpressed in many tumor types, has gained significant attention. In this work, we report design and development of theranostic gold nanostructures functionalized with PD-L1-targeting peptides (PTP, sPTP, and rPTP) whose sequences were identified combining structural analysis of the PD-1\/PD-L1 interaction interface and molecular dynamics simulations. This is because the design of functional nanostructures for protein targeting requires a precise understanding of how molecular recognition is affected by ligand organization at interfaces; therefore, peptide design was guided not only by the selection of key residues involved in binding but also by the evaluation of peptide assemblies to explicitly account for the collective effects governing target recognition. Indeed, beyond conventional evaluation of protein\/single-peptide interaction, peptide clusters and surface-anchored monolayers were investigated to consider features like peptide assembly, organization, and reduced conformational freedom in the nanostructure\/PD-L1 interaction. Results indicate that peptide sequence and orientation critically determine monolayer organization and accessibility of the PD-L1 binding motif. The computational predictions were experimentally validated by synthesizing peptide-functionalized gold nanostructures and evaluating their targeting performance against MDA-MB-231 breast cancer cells over-expressing PD-L1, using the surface-enhanced Raman scattering technique: NS functionalized with PTPs achieved the targeting of approximately 85% of MDA-MB-231 cells at 100 pM nanostructure concentration, compared to 23% for those functionalized with rPTP, demonstrating a nearly four-fold difference attributable exclusively to peptide orientation on the nanostructure surface. The specific system investigated in this work establishes a computational framework for the rational design of peptide-functionalized nanostructures, providing insights into the collective behavior of peptide monolayers and offering a smart methodology that, while demonstrated here for targeting PD-L1, is in principle applicable to other protein targets.<\/jats:p>","DOI":"10.1021\/acsabm.6c01076","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:34:37Z","timestamp":1785854077000},"page":"7637-7649","source":"Crossref","is-referenced-by-count":0,"title":["Peptide-Functionalized Gold Nanoparticles Targeting PD-L1: Design via a Molecular Dynamic Driven Approach and Further Experimental Validation"],"prefix":"10.1021","volume":"9","author":[{"given":"Micaela","family":"Giannetti","sequence":"first","affiliation":[{"name":"University of Rome \u201cTor Vergata\u201d , , Via della Ricerca Scientifica , ,","place":["Rome, Italy, 00133"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6316-0525","authenticated-orcid":true,"given":"Marina","family":"Gobbo","sequence":"additional","affiliation":[{"name":"University of Padua , , Via F. Marzolo 1 , ,","place":["Padua, Italy, 35131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6247-5456","authenticated-orcid":true,"given":"Lucio","family":"Litti","sequence":"additional","affiliation":[{"name":"University of Padua , , Via F. Marzolo 1 , ,","place":["Padua, Italy, 35131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Caligiuri","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Oncologico di Aviano (CRO) IRCCS , , Via F. Gallini 2 , , ,","place":["Aviano, PN, Italy, 33081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Rizzolio","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Oncologico di Aviano (CRO) IRCCS , , Via F. Gallini 2 , , ,","place":["Aviano, PN, Italy, 33081"]},{"name":"Ca\u2019 Foscari University of Venice , , Via Torino 155 , ,","place":["Venice, Italy, 30172"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3355-4811","authenticated-orcid":true,"given":"Moreno","family":"Meneghetti","sequence":"additional","affiliation":[{"name":"University of Padua , , Via F. 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