Engineered protein corona by Bispecific Antibody endows liposome with enhanced tumor targeting ability and mitigated accelerated blood clearance effect

One of the major challenges in the development of active targeting nanomedicines is the plasma protein corona (PC), which might interfere with or diminish the targeting function. A novel strategy has emerged by precisely regulating the PC through the utilization of endogenous proteins, which is possible to transform the PC into an integral component that enhances targeting ability. However, the individual variability and fluctuating concentrations of endogenous proteins in plasma limit its practical application. In this study, we employed a bispecific antibody (BsAb) integrating mPEG-scFv (a single chain variable fragment to methoxy polyethylene glycol) and HER2-scFv (human epidermal growth factor receptor 2 scFv) to assembly with liposome. By pre-engineering the PC of liposomes, the targeting function to HER2 cells could be preserved during circulation. Notably, the PC formed by BsAb competitively inhibited the binding of endogenous anti-PEG antibodies, thereby reducing subsequent complement activation and alleviating the accelerated blood clearance (ABC) effect. In tumor-bearing mice, BsAb-sLip demonstrated significant accumulation in HER2 human ovarian cancer cells (SKOV3). In the presence of anti-PEG antibodies after liposome stimulation in mice, BsAb significantly mitigated the ABC effect with prolonged liposome circulation. Consistently, in human serum containing pre-existing anti-PEG antibodies, BsAb suppressed liposome-induced complement activation, inhibited macrophage phagocytosis, and maintained the targeting ability toward HER2 tumor cells. These findings indicated that the engineered PC strategy via BsAb represented an effective targeting approach improving the overall in vivo performance of nanomedicines.