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This limitation highlights the critical necessity for developing engineered materials that can facilitate efficient intra-axonal transport and trans-synaptic translocation. In this study, we report the design and synthesis of core\u2013shell\u2013shell upconversion nanoparticles (CSS-UCNPs) featuring a NaYF4:YbEr core sequentially coated with active NaYF4:YbNd and inert NaYF4 shells. To achieve neuron-specific targeting, the architecture was surface-functionalized with poly(ethylene glycol) (PEG)-maleimide and conjugated to the RVG29 peptide (CSS-PEG-RVG29). Characterization by transmission electron microscopy, dynamic light scattering, and spectroscopic analyses confirmed uniform particle size (42.9 nm radius) and efficient upconversion luminescence (\u03bbex = 808 nm, \u03bbem = 500\u2212575 nm). In vitro assays demonstrated low cytotoxicity in Neuro2a, NSC34, and C6 cell lines at concentrations up to 500 \u03bcg\/mL, enhanced cellular uptake mediated by RVG29, and no detectable alterations in spinal neuronal action potential firing, as assessed by patch-clamp electrophysiology. In vivo, intrafascicular injection into the mouse sciatic nerve (2 mg\/mL, 2 \u03bcL) resulted in nanoparticle transport to the dorsal part of the spinal cord, with localization in higher regions of the central nervous system (CNS) and cortices, as visualized by multiphoton microscopy. In contrast, control experiments utilizing scrambled RVG29-conjugated nanoparticles demonstrated negligible accumulation within the CNS. These findings establish CSS-PEG-RVG29 as a promising platform for peripheral-to-CNS cargo delivery, with broad potential applications.<\/jats:p>","DOI":"10.1021\/jacsau.6c00949","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:02:27Z","timestamp":1787241747000},"page":"5295-5306","source":"Crossref","is-referenced-by-count":0,"title":["Transneuronal Transport of Ligand-Conjugated Upconversion\nNanoparticles from the Peripheral to the Central Nervous System"],"prefix":"10.1021","volume":"6","author":[{"given":"Haitao","family":"Liu","sequence":"first","affiliation":[{"name":"Hong Kong Baptist University , , , ,","place":["Kowloon, Hong Kong SAR, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengde","family":"Li","sequence":"additional","affiliation":[{"name":"Hong Kong Baptist University , , , ,","place":["Kowloon, Hong Kong SAR, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Hong Kong Baptist University , , , ,","place":["Kowloon, Hong Kong SAR, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Hamidi","sequence":"additional","affiliation":[{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United States, 33602"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7086-2170","authenticated-orcid":true,"given":"Angelo H.","family":"ALL","sequence":"additional","affiliation":[{"name":"Hong Kong Baptist University , , , ,","place":["Kowloon, Hong Kong SAR, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"issue":"40","key":"2026092808095500500_cit1","doi-asserted-by":"publisher","first-page":"35306","DOI":"10.1021\/acsnano.5c13559","article-title":"Intraneuronal Nanotracers\nin Axonal Transport","volume":"19","author":"Yi","year":"2025","journal-title":"ACS Nano"},{"issue":"1","key":"2026092808095500500_cit2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-022-01418-4","article-title":"BDNF-dependent Modulation of Axonal Transport is Selectively\nImpaired in ALS","volume":"10","author":"Tosolini","year":"2022","journal-title":"Acta Neuropathol. 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