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Employing a synthetic approach integrating advanced chemistries and bespoke in vitro biological assays, we developed versatile transferrin-conjugated polymeric nanoparticles designed for both blood\u2013brain barrier (BBB) penetration and GBM targeting. First, tunable azido-functional polymeric nanoparticles were synthesized through reversible addition\u2013fragmentation chain-transfer (RAFT)-mediated polymerization-induced self-assembly (PISA). Subsequently, holo-transferrin, modified with a diarylcyclooctyne (DBCO)-modified polyethylene glycol (PEG) linker, was conjugated onto the polymeric nanoparticles through copper-free click chemistry. The transferrin-functionalized polymeric nanoparticles were conjugated with doxorubicin via a pH-sensitive imine bond and displayed a pH-responsive drug release. Evaluation of cellular targetability, cytocompatibility, cytotoxicity, and the anticancer effect on GBM after crossing the BBB was conducted through a series of in vitro platforms of increasing physiological complexity: 2D cell culture, a static Transwell model, and a dynamic microfluidic BBB-GBM-on-a-chip model, utilizing immortalized human brain microvascular endothelial cells (hCMEC\/D3) and malignant glioma cells (U87-MG). Our results demonstrate the potential of the transferrin-conjugated polymeric nanoparticles in facilitating doxorubicin delivery across the BBB and enhancing cytotoxicity on GBM while concurrently mitigating the adverse side effects on the BBB associated with free doxorubicin.<\/jats:p>","DOI":"10.1021\/acsabm.6c01007","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:02:01Z","timestamp":1785862921000},"page":"7616-7628","source":"Crossref","is-referenced-by-count":0,"title":["Transferrin-Conjugated Polymeric Nanoparticles via Polymerization-Induced Self-Assembly for Enhanced BBB Transport and Glioblastoma Therapy"],"prefix":"10.1021","volume":"9","author":[{"given":"Weisen","family":"Zhang","sequence":"first","affiliation":[{"name":"Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]},{"name":"Commonwealth Scientific and Industrial Research Organisation (CSIRO) , , ,","place":["Clayton, Victoria, Australia, 3168"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6113-0584","authenticated-orcid":true,"given":"Lewis D.","family":"Blackman","sequence":"additional","affiliation":[{"name":"Commonwealth Scientific and Industrial Research Organisation (CSIRO) , , ,","place":["Clayton, Victoria, Australia, 3168"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya","family":"Ardana","sequence":"additional","affiliation":[{"name":"Commonwealth Scientific and Industrial Research Organisation (CSIRO) , , ,","place":["Clayton, Victoria, Australia, 3168"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douer","family":"Zhu","sequence":"additional","affiliation":[{"name":"Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Commonwealth Scientific and Industrial Research Organisation (CSIRO) , , ,","place":["Clayton, Victoria, Australia, 3168"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-3864","authenticated-orcid":true,"given":"Charlotte C.","family":"Williams","sequence":"additional","affiliation":[{"name":"Commonwealth Scientific and Industrial Research Organisation (CSIRO) , , ,","place":["Clayton, Victoria, Australia, 3168"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4183-1858","authenticated-orcid":true,"given":"Ziqiu","family":"Tong","sequence":"additional","affiliation":[{"name":"Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1536-7804","authenticated-orcid":true,"given":"Nicolas H.","family":"Voelcker","sequence":"additional","affiliation":[{"name":"Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]},{"name":"Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility , , ,","place":["Clayton, Victoria, Australia, 3168"]},{"name":"Monash University , , , ,","place":["Clayton, Victoria, Australia, 3800"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5511-5281","authenticated-orcid":true,"given":"Lars","family":"Esser","sequence":"additional","affiliation":[{"name":"Monash University , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]},{"name":"Commonwealth Scientific and Industrial Research Organisation (CSIRO) , , ,","place":["Clayton, Victoria, Australia, 3168"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"Supplement_1","key":"2026081707155534100_cit1","doi-asserted-by":"publisher","first-page":"iv1","DOI":"10.1093\/neuonc\/noaa200","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013\u20132017","volume":"22","author":"Ostrom","year":"2020","journal-title":"Neuro-Oncol."},{"key":"2026081707155534100_cit2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105780","article-title":"Glioblastoma Multiforme (GBM): An Overview of Current Therapies and Mechanisms of Resistance","volume":"171","author":"Wu","year":"2021","journal-title":"Pharmacol. 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