Chiral Artificial Antigen-Presenting Cells Enhancing Tumor Immunotherapy: Evasion of Macrophage Uptake through Inhibition of Serum Protein Corona Formation

Biomimetic artificial antigen-presenting cells (aAPCs) have emerged as a promising platform for the immune system activation and modulation. However, abundant serum proteins in the living body prefer to adsorb on the aAPC surface to form a protein corona, leading to rapid clearance of aAPCs by mononuclear phagocytes, causing inefficient tumor immunotherapy by aAPCs. To achieve long-lasting antitumor immunity, chiral aAPCs with left-handed (aAPCs-L) or right-handed (aAPCs-D) helices are constructed via coassembly, chiral induction, chiral memory, and a click reaction. aAPCs-L can efficiently prevent the formation of a protein corona since the left-handed helix of aAPCs-L and the right-handed helix of serum proteins are structurally mismatched. Compared with aAPCs-D and achiral aAPCs (aAPCs-R), aAPCs-L can extend the blood circulation half-life from 4.15-4.72 h to more than 24 h via evading macrophage uptake and clearance, performing sustained activation of antitumor immune response. In vivo treatment with aAPCs-L results in invisible residual melanoma on day 25 (but 947.3 ± 122.8 mm² residual melanoma for aAPCs-R and 656.1 ± 135.0 mm² residual melanoma for aAPCs-D). This study demonstrates that incorporating the chiral structure into the design of aAPCs improves pharmacokinetics and enhances the efficacy of tumor immunotherapy, which provides useful insights into the development of advanced biomedical materials for cancer treatment.