Polyphosphorylcholine-modified liposomes for glioblastoma-targeted siRNA delivery across the blood-brain barrier.

Liposomes represent versatile drug delivery shuttles in clinics for cancer therapy. Nevertheless, traditional PEG-modified liposomes encounter difficulties, including (1) poor blood-brain barrier (BBB) transcytosis and tumor targeting without ligand-decoration; (2) accelerated blood clearance (ABC) resulting from anti-PEG antibodies and complement proteins. To overcome these challenges, we employed a ligand-free, BBB-permeable, and glioblastoma (GBM)-targeting zwitterionic polyphosphorylcholine (PMPC)-modified liposomal formulation for siRNA delivery (PMPC-Lipo@siRNA). PMPC-modified formulation leverages interactions with nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) to achieve effective BBB transcytosis and targeted tumor accumulation. Unlike anti-PEG antibodies-induced immunogenicity, PMPC modification successfully circumvents opsonin recognition, which potentially translates into their extended blood circulation and improved therapeutic responses. By targeting the PLK1 oncogene, PMPC-Lipo@siPLK1 effectively induced apoptosis through PLK1 inhibition, significantly extending the median survival of mice in both orthotopic human U87MG and patient-derived CSC2 stem cell xenograft models. Overall, PMPC-modified liposomes provide an effective ligand-free platform for GBM-targeted siRNA delivery by combining prolonged systemic circulation with intrinsic brain-targeting capability, highlighting their potential for RNAi-based therapy against GBM.