LPC-engineered liposomes activate transcytosis for paclitaxel brain delivery and potentiation of TTFields/TMZ via TALECT regimen in glioblastoma

<b>Rationale:</b> Tumor Treating Fields (TTFields) in combination with temozolomide (TMZ) provides significant survival benefits in glioblastoma (GBM), but prolonged daily use of TTFields compromises patient compliance and cost-effectiveness. Paclitaxel (PTX) has potential synergistic effects with TTFields, but its efficacy is limited by the blood-brain barrier (BBB). The BBB penetration efficiency of receptor-mediated nanocarriers is limited by low endocytosis activity and lysosomal entrapment in brain endothelial cells. <b>Methods:</b> To overcome this limitation, we developed lysophosphatidylcholine (LPC)-engineered liposomes (LPC-Lipo) to activate brain endothelial transcytosis for BBB crossing PTX delivery and established a paclitaxel liposomes-electric fields-TMZ (TALECT) regimen for TTFields-based GBM therapy. The transcytosis behavior and mechanism of LPC-Lipo were investigated in both <i>in vitro</i> and <i>in vivo</i> BBB models. <i>In vivo</i> PTX delivery efficiency of LPC-Lipo and the therapeutic efficacy of TALECT regimen were evaluated in a GBM patient-derived xenograft model. <b>Results:</b> Leveraging our findings that LPC can activate brain endothelial transcytosis, LPC-Lipo was developed and exhibited enhanced transcytosis efficiency through accelerated endocytosis and directional trafficking to recycling endosomes (bypassing lysosomes) mediated by p62/SQSTM1, thereby achieving efficient BBB penetration. PTX-loaded LPC-Lipo achieved effective GBM suppression, and this efficacy was replicated in the clinical-grade Lipusu^® upon LPC engineering. Integrating optimized PTX delivery with the TTFields/TMZ combination established the TALECT regimen. TALECT therapy achieved potent therapy outcomes while reducing daily TTFields exposure by 75%. This efficacy stems from PTX's dual sensitization: (1) to TTFields via microtubule disruption-induced mitotic arrest, and (2) to TMZ by inhibiting DNA damage repair. <b>Conclusions:</b> This work presents a novel transcytosis-activating platform for BBB penetration and proposes the clinically translatable TALECT regimen, advancing the cost-effectiveness of TTFields-based GBM therapy.