Self-Promoted Targeting Delivery of Nanodrug Through Chemotherapeutic Upregulation of CD47 for Triple Negative Breast Cancer Therapy

The high heterogeneity of receptor expression and varied chemotherapeutic sensitivity seriously compromise the therapeutic outcome of triple-negative breast cancer (TNBC)-targeting nanodrugs. In this work, a TNBC-targeting nanodrug (designated as CPU) equipped with self-promoted targeting property through chemotherapeutic upregulation of CD47 is constructed, enabling synergistic chemo/photodynamic therapy. Specifically, the hydrophobic docetaxel (DOC), which can upregulate the expression of CD47 in TNBC cells, is loaded in the nanomicelles (designated as P-Pep) assembled from a protoporphyrin IX (PPIX)-labeled amphiphilic chimeric peptide of Fmoc-K(PPIX)-AWSATWSNYWRH, obtaining the ca. 196 nm CPU. Aided by the enhanced permeability and retention effect and guidance of CD47-binding peptide sequence, CPU is verified to prefer to accumulate in CD47 overexpressed TNBC cells, which can recruit more CPU by upregulating CD47 expression post-treatment of DOC. Both in vitro and in vivo results demonstrate the superior tumor targeting ability, which can extensively amplify chemotherapeutic and photodynamic therapeutic effects while evading obvious adverse effects. The self-promoted targeting strategy will inspire the design of nanodrugs for the personalized therapy of tumors with high heterogeneity and resistance. A CD47-based triple-negative breast cancer (TNBC)-targeting nanodrug (designated as CPU) equipped with self-promoted targeting property through docetaxel-mediated chemotherapeutic upregulation of CD47 is constructed for synergistic chemo/photodynamic therapy, enabling a robust TNBC eradication effect both in vitro and in vivo. This strategy will inspire the development of innovative nanodrugs for the personalized therapy of tumors with high heterogeneity and resistance.image