multitargeted nanoparticles deliver synergistic drugs across the bloodbrain barrier to brain metastases of triple negative breast cancer cells and tumorassociated macrophages patients with brain metastases of triple negative breast cancer tnbc have a poor prognosis owing to the lack of targeted therapies the aggressive nature of tnbc and the presence of the bloodbrain barrier bbb that blocks penetration of most drugs additionally infiltration of tumorassociated macrophages tams promotes tumor progression here a terpolymerlipid hybrid nanoparticle tpln system is designed with multiple targeting moieties to first undergo synchronized bbb crossing and then actively target tnbc cells and tams in microlesions of brain metastases in vitro and in vivo studies demonstrate that covalently bound polysorbate 80 in the terpolymer enables the lowdensity lipoprotein receptormediated bbb crossing and tamtargetability of the tpln conjugation of cyclic internalizing peptide irgd enhances cellular uptake cytotoxicity and drug delivery to brain metastases of integrinoverexpressing tnbc cells irgdtpln with coloaded doxorubicin dox and mitomycin c mmc irgddmtpln exhibits higher efficacy in reducing metastatic burden and tams than nontargeted dmtpln or a free doxmmc combination irgddmtpln treatment reduces metastatic burden by 6fold and 19fold and increases host median survival by 13fold and 16fold compared to dmtpln or free doxmmc treatments respectively these findings suggest that irgddmtpln is a promising multitargeted drug delivery system for the treatment of integrinoverexpressing brain metastases of tnbc