Engineered microalgal extracellular vesicles for efficient doxorubicin delivery and improved therapeutic efficacy in breast cancer

Extracellular vesicles (EVs) have emerged as versatile and biocompatible nanocarriers for drug delivery, offering significant advantages over synthetic nanoparticles, which often suffer from rapid clearance, immunogenicity, and limited clinical translation. In this study, we introduce nanoalgosomes, a new class of EVs derived from the marine microalga Tetraselmis chuii , as biogenic carriers for doxorubicin delivery in breast cancer models. Nanoalgosomes exhibit high stability, in vivo biocompatibility, and efficient cargo-loading capacity, making them ideal for therapeutic applications. We optimized doxorubicin-loading strategy, preserving the structural integrity of nanoalgosomes while achieving efficient drug incorporation. Compared to free drug treatments, doxorubicin-loaded nanoalgosomes significantly enhanced drug uptake and its therapeutic effects in breast cancer models. Notably, doxorubicin-loaded nanoalgosomes exhibited a markedly enhanced chemotherapeutic potency compared to free doxorubicin. In 2D tumor cell cultures, nanoalgosomes reduced the doxorubicin the half maximal inhibitory concentration (IC 50 ) by approximately 8-fold. In 3D tumor spheroids, which more closely recapitulate tumor architecture and drug penetration, the IC 50 decreased from >2.5 μM for free doxorubicin to 0.7 μM for the doxorubicin-loaded nanoalgosomes, resulting in about 60% spheroid volume reduction. The superior efficacy of doxorubicin-loaded nanoalgosomes was further validated in vivo in Caenorhabditis elegans , where the IC 50 decreased 3-fold for the doxorubicin-loaded nanoalgosomes. These results highlight nanoalgosomes as a sustainable and scalable next-generation drug delivery platform for precision oncology, offering a promising alternative to synthetic nanocarriers. • Nanoalgosomes from T. chuii are natural carriers for chemotherapy drugs. • Optimized loading preserved integrity, achieved high drug encapsulation efficiency. • Doxorubicin-loaded nanoalgosomes improved efficacy in 2D and 3D cancer models. • In vivo assays demonstrated that C. elegans germline apoptosis was induced at a threefold lower dose. • Delivery by nanoalgosomes increased selectivity, reduced off-target cell toxicity.