Exosomes displaying native EGF enhance doxorubicin's therapeutic efficacy and reduce cardiotoxicity

Doxorubicin (DOX) is one of the most potent chemotherapeutic agents for cancer treatment. However, its cumulative and often irreversible, life-threatening cardiotoxicity significantly limits its clinical applications. While strategies like dose reduction, iron chelation, and liposome encapsulation have aided in mitigating cardiotoxicity to certain extent, they are associated with decreased therapeutic efficacy and potential cancer relapse, the risk of developing secondary malignancy, and the incidence of the Hand-foot syndrome. Exosomes (Exo) are naturally occurring nanoparticles that can be engineered to display targeting moieties on their surface, thereby enhancing drug delivery efficacy. We aimed to develop an exosomal DOX formulation targeting broad epidermal growth factor receptor (EGFR) variants to enhance its anti-tumor efficacy and minimize cardiotoxicity.

The native 53-amino-acid EGF was decorated on the surface of exosomes by genetically engineering exosome-producing A549 cells. The EGF-Exo was effectively internalized by tumor cell lines in a manner dependent on EGFR expression levels, and exhibited enhanced accumulation in xenograft A549 tumors relative to the heart, with minimal cardiac accumulation. When loaded with DOX, these engineered exosomes were rapidly internalized, inducing higher apoptosis in A549 cells compared to liposomal-DOX. Upon systemic administration in an A549 xenograft mouse model, EGF-Exo-DOX exhibited enhanced accumulation in tumors relative to the heart, with minimal cardiac accumulation, significantly reducing tumor burden, mitigating DOX-induced cardiotoxicity, and exhibiting no tumorigenic effects. This favorable therapeutic profile is primarily attributed to DOX-induced apoptosis.

Our findings demonstrate that tumor-derived exosomes engineered with EGF on their surface enable targeted drug delivery to tumors with high EGFR expression. Although the exosomes modestly increase cell proliferation in vitro, the EGF-Exo-DOX formulation exhibits enhanced tumor accumulation relative to the heart, minimal cardiac uptake, and shows no tumorigenic effects in vivo. Compared to Lipo-DOX, a widely used clinical formulation of liposomal DOX in China, EGF-Exo-DOX demonstrates superior cellular uptake, greater induction of tumor cell apoptosis, and improved anti-tumor efficacy. These results highlight the potential of engineered exosomes as a targeted drug delivery platform for patients with EGFR-overexpressing tumors.