Cleavable-Branched Polymer-Modified Liposomes Reduce Accelerated Blood Clearance and Enhance Photothermal Therapy

In recent years, cationic liposomes have been successfully used as delivery platforms for mRNA vaccines. Poly(ethylene glycol) (PEG)-lipid derivatives are widely used to enhance the stability and reduce the toxicity of cationic liposomes. However, these derivatives are often immunogenic, triggering the rise of anti-PEG antibodies. Understanding the role and impact of PEG-lipid derivatives on PEGylated cationic liposomes is key to solving the PEG dilemma. In this study, we designed linear, branched, and cleavable-branched cationic liposomes modified with PEG-lipid derivatives and investigated the effect of the liposome-induced accelerated blood clearance (ABC) phenomenon on photothermal therapy. Our study indicated that the linear PEG-lipid derivatives mediated the effect of photothermal therapy by stimulating splenic marginal zone (MZ) B cells to secrete anti-PEG antibodies and increasing the level of IgM expression in the follicular region of the spleen. However, the cleavable-branched and branched PEG-lipid derivatives did not activate the complement system and avoided the ABC phenomenon by inducing noticeably lower levels of anti-PEG antibodies. The cleavable-branched PEGylated cationic liposomes improved the effect of photothermal therapy by reversing the charge on the liposome surface. This detailed study of PEG-lipid derivatives contributes to the further development and clinical application of PEGylated cationic liposomes.