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While the brain is shielded from many toxins and viruses by the blood-brain barrier (BBB), therapeutics are being created that exploit natural bypass mechanisms by forming complexes with cell-penetrating peptides (CPPs) derived from viruses. Neurological diseases often impact specific proteins in the brain; however, current CPPs lack the ability to selectively target precise cellular macromolecules. As a result, they are distributed broadly throughout the brain and cause off-target side effects. Neurotropic CPPs derived from the rabies virus glycoprotein (RVG) can access the brain by binding to plasma membrane targets, including, but not exclusively, nicotinic acetylcholine receptors (nAChRs). To overcome this barrier of minimal target selectivity, we designed several chimeric peptides composed of regions from the RVG and \u03b1-bungarotoxin, an \u03b17 subtype-selective protein. Using human nAChRs expressed in\n                  <jats:italic>Xenopus laevis<\/jats:italic>\n                  oocytes, we screened the selectivity of our peptides using two-electrode voltage clamp electrophysiology. We identified a peptide with improved \u03b17 nAChR subtype selectivity and apparent potency compared to the control RVG peptide. Using mammalian Neuro-2a cells, we demonstrated that our peptide depends on \u03b17 nAChR plasma membrane expression to internalize and carry small-molecule payloads into the neuronal-like cells, without significant cytotoxic effects. Our novel \u03b17 nAChR subtype-selective CPP may be useful in research applications requiring cargo delivery. Translationally, our \u03b17 nAChR selective CPP holds potential to be a dual drug delivery system to transport cargo into the brain for the treatment of neurological diseases.\n                <\/jats:p>","DOI":"10.1101\/2025.08.08.669423","type":"posted-content","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T05:50:12Z","timestamp":1754891412000},"source":"Crossref","is-referenced-by-count":1,"title":["Development of a novel alpha7-nicotinic acetylcholine receptor-selective cell-penetrating peptide for intracellular cargo transport"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7079-1387","authenticated-orcid":false,"given":"Lahra","family":"Weber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany C. 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