Macrophage membrane coating enhances the therapeutic effects of Houttuynia cordata exosome-like nanovesicles against triple-negative breast cancer

The clinical management of triple-negative breast cancer (TNBC) is often limited by the adverse effects and suboptimal efficacy of conventional drugs. In this study, we isolated and purified natural exosome-like nanovesicles (CELNs) from <i>Houttuynia cordata</i> Thunb. (HCT), which primarily comprise proteins, lipids, and RNAs. Proteomic profiling confirmed that CELNs retain a wide spectrum of bioactive components from HCT. These nanovesicles demonstrated high biocompatibility and an enhanced capacity to modulate DNA template transcription. To improve targeted delivery, CELNs were coated with macrophage membranes, generating MCELNs, which significantly promoted their uptake by TNBC cells. Both MCELNs and CELNs effectively inhibited cell viability and colony formation, induced cell cycle arrest and apoptosis, and suppressed TNBC growth, with MCELNs exhibiting stronger antitumor activity. Transcriptome analysis revealed that MCELNs treatment resulted in significant enrichment of differentially expressed genes related to DNA damage and repair pathways. Consistent with this, both MCELNs and CELNs upregulated the protein expression of γ-H2AX, p-ATR, p-CHK1, p21, cleaved PARP1, and cleaved caspase 3, while downregulating CDC25C, CDK4, and full-length PARP1. These effects were substantially reversed by the DNA damage protective agent MPA. Mechanistically, MCELNs and CELNs exert anti-TNBC effects primarily by triggering DNA damage to cause cell cycle arrest and apoptosis. Collectively, the present study establishes the potential of <i>Houttuynia cordata</i>-derived exosome-like nanovesicles as a natural therapeutic platform against TNBC, with macrophage membrane coating further augmenting their efficacy through biomimetic targeting. MCELNs may represent a promising drug delivery strategy for enhancing treatment efficacy while minimizing systemic toxicity in breast cancer therapy.