Honeysuckle-derived vesicle-like nanoparticle and their hybrid vesicle as novel drug delivery systems for glioma therapy.

Gliomas present a formidable challenge in oncology due to their immunosuppressive tumor microenvironment and the restricted delivery of therapeutics across the blood-brain barrier. Here, we report a novel hybrid nanoplatform (HEV) for synergistic chemo-immunotherapy, constructed by integrating honeysuckle-derived vesicle-like nanoparticles (HDVN) with paclitaxel (PTX)-loaded liposomes via PEG-mediated fusion. HDVN, extracted from Lonicera japonica Flos using sucrose gradient ultracentrifugation, measured 104 ± 2.1 nm in diameter and carried functional miRNAs, including miRNA2911, capable of modulating tumor-associated macrophage (TAM) polarization through the JNK and p38 MAPK pathway. The resulting HEV achieved an encapsulation efficiency of 86.58 ± 0.06% and were administered intranasally to exploit nasal-to-brain (N2B) delivery and enhanced permeability effects. In vitro, HEV exhibited potent cytotoxicity against C6 glioma cells (IC50: 3.93 µg/mL) and promoted M1 polarization of TAM, upregulating CD80, CD86, and MHC-II while suppressing CD206. In vivo, HEV significantly inhibited tumor growth in C6 glioma-bearing mice, extending median survival from 21 to 66 days, with reduced systemic toxicity compared to free paclitaxel. miRNA sequencing and KEGG pathway analysis confirmed the cross-kingdom immunomodulatory function of HDVN, contributing to the synergistic therapeutic effect. This study establishes HDVN and HEV as a pioneering nanoplatform for targeted chemo-immunotherapy in glioma, offering a promising strategy with potential for clinical translation.