Abstract

Anchoring-conjugation strategy, characterized by benign hydrophobic membrane anchoring and swift covalent drug-coupling, has been extensively practiced to attach therapeutic agents to cell surfaces in cell-based combination therapies. However, this approach faces significant challenges in phagocytic cells due to their enhanced membrane fluidity, which destabilizes the hydrophobic interactions and causes premature payload dissociation from cells, ultimately impairing drug delivery. This research proposes a biomimetic trident anchoring lipid featuring three hydrophobic tail chains to amplify hydrophobic interactions with the phagocyte membrane. The trident anchoring lipid thus results in robust membrane anchoring and accordingly extends drug retention on the neutrophil surface without compromising cell viability or physiological functions both in vitro and in vivo. Leveraging the inflammatory tendency of neutrophils toward the tumor vasculature, the strengthened drug conjugation facilitates effective drug delivery and site-specific release to the tumor vasculature in breast cancer models, demonstrating potent anti-angiogenic and anti-tumor efficacy. This innovative trident anchoring lipid establishes a versatile and stable drug-conjugation method for bolstering the therapeutic outcomes of neutrophil-based and potentially other cell-based combination therapies.