Biomimetic platelet-membrane camouflaged ivermectin nanocrystals for tumor homing and breast cancer management.

Leveraging the intrinsic platelet-cancer cell crosstalk through platelet membrane-coated nanosystems offers a promising avenue for targeted drug delivery, particularly against triple-negative breast cancer, the most aggressive highly metastatic breast cancer subtype. In parallel, repurposing the antiparasitic ivermectin (Ivm) for anticancer applications is hindered by poor solubility and high toxicity, restricting its parenteral administration. In this study, ivermectin nanocrystals (Ivm-NC) were first developed to enhance drug solubility and systemic delivery. Afterwards, platelet-membrane was employed for realizing platelet-mimetic-camouflaged PMV/Ivm-NC for active-targeted tumor homing, immune evasion and higher biocompatibility. The innovative PMV/Ivm-NC presented optimum particle-size and zeta-potential, while exhibiting a sustained release pattern. Successful coating and retention of platelet membrane proteins was confirmed by SDS-PAGE profiling and immunocytochemistry for the platelet-membrane-protein P-selectin. In vitro studies for PMV/Ivm-NC demonstrated higher selective-cytotoxicity (IC 2.89 ± 0.38 µg/mL) and anti-migratory potential on MDA-MB-231 cells, and cytocompatibility on normal human fibroblasts vs. uncoated Ivm-NC. In 4T1-tumor-bearing BALB/c mice, PMV-functionalization fostered preferential tumor-homing and reduced off-target distribution, compared to uncoated-NC. In addition, PMV/Ivm-NC secured pronounced tumor-growth inhibition, down-regulation of oncogenic markers (VEGF and cyclin D1), upregulation of pro-apoptotic Bax and caspase-3, and enhanced immune-infiltration of CD4 and CD8 T-cells, suggesting Ivm-induced immunogenic cell death. Histological evaluation confirmed higher tumor-necrosis and lower mitotic-count, as well as a notable lung-antimetastatic activity. Serum biochemistry and histopathology confirmed favorable biocompatibility. Together, our findings highlight PMV/Ivm-NC as a promising biomimetic-camouflaged nanoplatform for harnessing Ivm repurposed anticancer immunotherapy and reducing possible toxicity with selective, active targeting of triple negative breast cancer.