{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:03:40Z","timestamp":1784527420210,"version":"3.55.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cysteine-rich miniproteins from venomous animals are promising therapeutic scaffolds due to their compact structure, high stability, and low immunogenicity. Chlorotoxin (CTX), a miniprotein derived from scorpion venom, selectively targets glioblastoma by binding matrix metalloproteinase-2 (MMP-2), an invasion-associated enzyme overexpressed in \u223c80% of glioblastomas. CTX has been utilized in tumor imaging, drug delivery, and immunotherapy, including its incorporation into chimeric antigen receptor (CAR) constructs. CTX-based CAR show potent MMP-2\u2013dependent cytotoxicity in glioblastoma models. We hypothesized that affinity maturation of CTX via phage display could enhance MMP-2 binding and improve CAR T-cell performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A CTX-based phage display library (\u223c1.3 million variants) was screened against immobilized MMP-2. A lead variant, CTXA8, was recombinantly expressed and tested for binding specificity against a panel of off-target proteins. Its cellular uptake and localization were evaluated, followed by incorporation into CAR constructs in both single-unit and tandem formats (eCTXA8-CAR). The cytotoxicity of CTX-, CTXA8-, and eCTXA8-CAR T cells was assessed against glioblastoma cell lines and primary patient-derived tumor cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Screening identified CTXA8, which demonstrated a 4.4-fold increase in MMP-2 affinity and reduced off-target binding relative to CTX. Fluorescent CTXA8 showed 2.4\u20133.5-fold greater uptake in glioblastoma cells than CTX. Among the CAR constructs tested, eCTXA8 induced the highest IFN-\u03b3 release. eCTXA8-CAR T-cells consistently outperformed CTX-CAR and non-transduced T cells in cytotoxicity assays, especially at low effector-to-target ratios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that directed evolution of CTX can produce high-affinity, selective MMP-2 ligands suitable for next-generation CAR T-cell therapies. CTXA8-based CARs offer enhanced anti-tumor efficacy, supporting their potential in overcoming challenges in solid tumor immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbioe.2026.1866928","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:34:55Z","timestamp":1784525695000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Directed evolution of chlorotoxin enhances MMP-2 recognition and improves CAR-T-cell activity in glioblastoma models in vitro"],"prefix":"10.3389","volume":"14","author":[{"given":"Anna","family":"Hajdara","sequence":"first","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1rp\u00e1d","family":"Sz\u00f6\u0151r","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty If Medicine, University of Debrecen","place":["Debrecen, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3zsef","family":"Mur\u00e1nyi","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Bruny\u00e1nszki","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor Z.","family":"R\u00e1cz","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Cioca","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambrus","family":"Gordos","sequence":"additional","affiliation":[{"name":"Doctoral School of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natali","family":"Bata","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00e9mi","family":"Nagy","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imre","family":"Fedorcs\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Neurointervention, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"Sipos","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Neurointervention, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1t\u00e9","family":"Kisgy\u00f6rgy","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty If Medicine, University of Debrecen","place":["Debrecen, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rton","family":"Megyeri","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zal\u00e1n","family":"P\u00e9terfi","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e1ndor","family":"Farkas","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Horny\u00e1k","sequence":"additional","affiliation":[{"name":"VRG Therapeutics Ltd.","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s40478-023-01605-x","article-title":"On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells","volume":"11","author":"Ah-Pine","year":"2023","journal-title":"Acta Neuropathol. 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