{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:15:42Z","timestamp":1775542542856,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Science and Technology Development Program of Jilin Province","award":["No.20200404114YY, No. 20200301029RQ"],"award-info":[{"award-number":["No.20200404114YY, No. 20200301029RQ"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cell penetrating peptides (CPPs) are peptides that can directly adapt to cell membranes and then permeate into cells. CPPs are usually covalently linked to the surface of nanocarriers to endow their permeability to the whole system. However, hybrids with lipids or polymers make the metabolism much more sophisticated and even more difficult to determine. In this study, we present a continuous sequence of 18 amino acids (FFAARTMIWY(d-P)GAWYKRI). It forms nanospheres around 170 nm, which increase slightly after loading with siRNA and DOX. Notably, it can be internalized by cancer cells mainly through electronic interactions and PD-L1-mediated endocytosis. Compared with poly-l-lysine and polyethyleneimine, it has a much higher efficiency (about four times) of gene transduction while lowering toxicity. In the treatment of cancer, it causes apoptosis (21%) and inhibits the expression of SURVIVIN protein in vitro. In vivo, it shows good biocompatibility as there are no changes in mice\u2019s body weight. When administering peptide-siRNA-DOX, tumor growth is inhibited the most (about three times). These results above prove the sequence to be a good candidate for gene therapy and drug delivery.<\/jats:p>","DOI":"10.3390\/ijms222413314","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T01:28:11Z","timestamp":1639358891000},"page":"13314","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cell Penetrating Peptide-Based Self-Assembly for PD-L1 Targeted Tumor Regression"],"prefix":"10.3390","volume":"22","author":[{"given":"Feng","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130012, China"},{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junfeng","family":"Ke","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130012, China"},{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengdong","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130012, China"},{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhao","family":"Han","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130012, China"},{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130012, China"},{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.drudis.2016.10.014","article-title":"miRNA nanotherapeutics for cancer","volume":"22","author":"Ganju","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s12951-021-00981-7","article-title":"Self-assembled fluorescent hybrid nanoparticles-mediated collaborative lncRNA CCAT1 silencing and curcumin delivery for synchronous colorectal cancer theranostics","volume":"19","author":"Jia","year":"2021","journal-title":"J. Nanobiotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4933","DOI":"10.1021\/acsbiomaterials.1c00880","article-title":"Selenomethionine-Modified Polyethylenimine-Based Nanoparticles Loaded with miR-132-3p Inhibitor-Biofunctionalized Titanium Implants for Improved Osteointegration","volume":"7","author":"Li","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5859","DOI":"10.1021\/acs.nanolett.1c01792","article-title":"Gold-Nanocluster-Mediated Delivery of siRNA to Intact Plant Cells for Efficient Gene Knockdown","volume":"21","author":"Zhang","year":"2021","journal-title":"Nano Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113572","DOI":"10.1016\/j.ejmech.2021.113572","article-title":"Amine-terminated dendritic polymers as promising nanoplatform for diagnostic and therapeutic agents\u2019 modification: A review","volume":"221","author":"Delyanee","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1021\/acsbiomaterials.1c00582","article-title":"Stimuli-Responsive and Highly Penetrable Nanoparticles as a Multifunctional Nanoplatform for Boosting Nonsmall Cell Lung Cancer siRNA Therapy","volume":"7","author":"Shi","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/sj.gt.3302054","article-title":"PEI\u2014A potent, but not harmless, mucosal immuno-stimulator of mixed T-helper cell response and FasL-mediated cell death in mice","volume":"10","author":"Regnstrom","year":"2003","journal-title":"Gene Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/jgm.237","article-title":"Side-effects of a systemic injection of linear polyethylenimine-DNA complexes","volume":"4","author":"Chollet","year":"2002","journal-title":"J. Gene Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1002\/(SICI)1521-3935(19981101)199:11<2565::AID-MACP2565>3.0.CO;2-G","article-title":"A novel modification of poly(L-lysine) leading to a soluble cationic polymer with reduced toxicity and with potential as a transfection agent","volume":"199","author":"Ferruti","year":"1998","journal-title":"Macromol. Chem. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1002\/pola.10301","article-title":"Discovery of dendrimers and dendritic polymers: A brief historical perspective","volume":"40","author":"Tomalia","year":"2002","journal-title":"J. Polym. Sci. Part A Polym. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ijpharm.2014.02.018","article-title":"The strategy to improve gene transfection efficiency and biocompatibility of hyperbranched PAMAM with the cooperation of PEGylated hyperbranched PAMAM","volume":"465","author":"Sun","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.jcis.2019.09.049","article-title":"Cyclic dipeptide nanoribbons formed by dye-mediated hydrophobic self-assembly for cancer chemotherapy","volume":"557","author":"Yang","year":"2019","journal-title":"J. Colloid Interface Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8860","DOI":"10.1002\/anie.201916111","article-title":"Hierarchical Self-Assembled Photo-Responsive Tubisomes from a Cyclic Peptide-Bridged Amphiphilic Block Copolymer","volume":"59","author":"Yang","year":"2020","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/s41467-017-01447-x","article-title":"Self-assembling dipeptide antibacterial nanostructures with membrane disrupting activity","volume":"8","author":"Schnaider","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4122","DOI":"10.1039\/c0sm01218a","article-title":"Self-assembly of amphiphilic peptides","volume":"7","author":"Hamley","year":"2011","journal-title":"Soft Matter."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1126\/science.1082387","article-title":"Casting Metal Nanowires within Discrete Self-Assembled Peptide Nanotubes","volume":"300","author":"Reches","year":"2003","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1021\/acsnano.5b00623","article-title":"Controlled Rod Nanostructured Assembly of Diphenylalanine and Their Optical Waveguide Properties","volume":"9","author":"Li","year":"2015","journal-title":"ACS Nano"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/adma.201502545","article-title":"Nanoarchitectonics for Dynamic Functional Materials from Atomic-\/Molecular-Level Manipulation to Macroscopic Action","volume":"28","author":"Ariga","year":"2016","journal-title":"Adv. Mater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1021\/nl035159z","article-title":"Formation of Closed-Cage Nanostructures by Self-Assembly of Aromatic Dipeptides","volume":"4","author":"Reches","year":"2004","journal-title":"Nano Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1039\/C5TB02240A","article-title":"Polycaprolactone fibers with self-assembled peptide micro\/nanotubes: A practical route towards enhanced mechanical strength and drug delivery applications","volume":"4","author":"Liberato","year":"2016","journal-title":"J. Mater. Chem. B"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D1098","DOI":"10.1093\/nar\/gkv1266","article-title":"CPPsite 2.0: A repository of experimentally validated cell-penetrating peptides","volume":"44","author":"Agrawal","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.bbamem.2006.01.006","article-title":"Mechanistic aspects of CPP-mediated intracellular drug delivery: Relevance of CPP self-assembly","volume":"1758","author":"Pujals","year":"2006","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Taylor, R.E., and Zahid, M. (2020). Cell Penetrating Peptides, Novel Vectors for Gene Therapy. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12030225"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.7150\/thno.13532","article-title":"Dual Receptor Recognizing Cell Penetrating Peptide for Selective Targeting, Efficient Intratumoral Diffusion and Synthesized Anti-Glioma Therapy","volume":"6","author":"Liu","year":"2016","journal-title":"Theranostics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.bbrc.2020.04.018","article-title":"Effect of the hairpin structure of peptide inhibitors on the blockade of PD-1\/PD-L1 axis","volume":"527","author":"Wang","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10205","DOI":"10.1021\/la4019162","article-title":"L-diphenylalanine microtubes as a potential drug-delivery system: Characterization, release kinetics, and cytotoxicity","volume":"29","author":"Silva","year":"2013","journal-title":"Langmuir"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"281","DOI":"10.7150\/thno.35568","article-title":"RNA Nanotechnology-Mediated Cancer Immunotherapy","volume":"10","author":"Lin","year":"2020","journal-title":"Theranostics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nbt.3802","article-title":"Overcoming cellular barriers for RNA therapeutics","volume":"35","author":"Dowdy","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.sbi.2016.06.001","article-title":"Cryo-electron microscopy for structure analyses of membrane proteins in the lipid bilayer","volume":"39","author":"Abe","year":"2016","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1002\/pola.29531","article-title":"Synthesis and Hierarchical Self-Assembly of Diphenylalanine-Based Homopolymer and Copolymers by RAFT Polymerization","volume":"57","author":"Yonenuma","year":"2019","journal-title":"J. Polym. Sci. Part A Polym. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1039\/b609047h","article-title":"Designing peptide-based nanomaterials","volume":"37","author":"Ulijn","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s40259-013-0058-x","article-title":"Targeting survivin in cancer: Novel drug development approaches","volume":"28","author":"Groner","year":"2014","journal-title":"BioDrugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1900500","DOI":"10.1002\/adhm.201900500","article-title":"Selective Cell Penetrating Peptide-Functionalized Envelope-Type Chimeric Lipopepsomes Boost Systemic RNAi Therapy for Lung Tumors","volume":"8","author":"Qiu","year":"2019","journal-title":"Adv. Healthc. Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5722","DOI":"10.1021\/ja211035w","article-title":"Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles","volume":"134","author":"Pan","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1080\/10837450.2018.1469147","article-title":"Conjugates of TAT and folate with DOX-loaded chitosan micelles offer effective intracellular delivery ability","volume":"24","author":"Zhang","year":"2019","journal-title":"Pharm. Dev. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1039\/c2cs35172b","article-title":"Design and properties of functional nanotubes from the self-assembly of cyclic peptide templates","volume":"41","author":"Chapman","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.1002\/anie.201913611","article-title":"Nanoassembly of Oligopeptides and DNA Mimics the Sequential Disassembly of a Spherical Virus","volume":"59","author":"Ni","year":"2020","journal-title":"Angew. Chem. Int. Ed."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13314\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:45:14Z","timestamp":1760168714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":38,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222413314"],"URL":"https:\/\/doi.org\/10.3390\/ijms222413314","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,10]]}}}