Polyphosphocholination of liposomic vehicles extends blood circulation, enhances cellular uptake, and lowers immunogenicity relative to PEGylation.

Intravenous liposomal drug delivery holds great promise for pharmaceutical efficacy, but faces challenges such as rapid clearance and immune system degradation. PEG-based liposome surface functionalization (PEGylation), currently the gold-standard and most widely-used approach to address these issues, is prone to reduced cellular uptake and accelerated bloodstream clearance (ABC) effect upon repeated administration due to immune activation. We demonstrate a novel liposome surface functionalization using poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) that significantly overcomes these limitations while maintaining comparable colloidal stability. Such polyphosphocholinated liposomes exhibit tunable cellular uptake, and prolonged blood circulation times, both modulated by polymer length, alongside reduced immunogenicity (lower IgM antibody elicitation) and a diminished ABC effect compared to PEG-liposomes. These polymer-length-dependent properties offer flexibility in optimizing drug delivery systems, positioning pMPCylated liposomes as a compelling alternative to PEGylated formulations with clear advantages for liposomal drug delivery therapeutics.