A Tumoricidal Lipoprotein Complex Electrostatically Stabilized on Mesoporous Silica as Nanotherapeutics and Nanoadjuvant for Potentiating Immunotherapy of Triple Negative Breast Cancer

Abstract

AbstractAs the most aggressive subtype, triple‐negative breast cancer (TNBC) without definitive targets represents a high probability of metastasis. Nevertheless, the presence of high‐level tumor‐infiltrating lymphocytes in the TNBC tumor microenvironment (TME) suggests patients may benefit from immunotherapy. In this study, bovine α‐lactalbumin coupled with oleic acid that forms tumoricidal lipid–protein complex (BAMLET) is electrostatically stabilized on the surface of amino‐functionalized mesoporous silica nanoparticles (MSN‐NH2). It is found that MSN‐NH2 may cause partial conformational changes of immobilized proteins due to electrostatic interactions. Therefore, BAMLET covered MSN‐NH2 (BMSN) as a drug cargo that can not only induce selectively oncolytic effect but kill tumor cells with rapid kinetics. Moreover, the hemolytic activity of BMSN conjugated with pre‐formed serum protein corona is largely reduced which may avoid the poor hemocompatibility caused by BAMLET. Furthermore, the in vivo study indicates that the combinational use of drug‐loaded BMSN and immune checkpoint small‐molecule inhibitor can efficiently inhibit the growth of solid TNBC tumors and activate immune response by sufficient infiltration of immune cells in the TME and prevent the seeding of circulating tumor cells. Therefore, the constructed BMSN provides an integrated nanotherapeutics and a nanoadjuvant with superior anticancer performance to combat TNBC.