Chemical conjugation mitigates immunotoxicity of chemotherapy via reducing receptor-mediated drug leakage from lipid nanoparticles

Immunotoxicity remains a major hindrance to chemotherapy in cancer therapy. Nanocarriers may alleviate the immunotoxicity, but the optimal design remains unclear. Here, we created two variants of maytansine (DM1)–loaded synthetic high-density lipoproteins (D-sHDL) with either physically entrapped ( E D-sHDL) or chemically conjugated ( C D-sHDL) DM1. We found that C D-sHDL showed less accumulation in the tumor draining lymph nodes (DLNs) and femur, resulting in a lower toxicity against myeloid cells than E D-sHDL via avoiding scavenger receptor class B type 1 (SR-B1)–mediated DM1 transportation into the granulocyte-monocyte progenitors and dendritic cells. Therefore, higher densities of lymphocytes in the tumors, DLNs, and blood were recorded in mice receiving C D-sHDL, leading to a better efficacy and immune memory of C D-sHDL against colon cancer. Furthermore, liposomes with conjugated DM1 ( C D-Lipo) showed lower immunotoxicity than those with entrapped drug ( E D-Lipo) through the same mechanism after apolipoprotein opsonization. Our findings highlight the critical role of drug loading patterns in dictating the biological fate and activity of nanomedicine.