Everolimus Delivery via Lignin Nanoparticles Enhances Antitumor Activity in Hormone Receptor-Positive Breast Cancer.

The mTOR inhibitor everolimus improved progression-free survival in patients with hormone receptor-positive breast cancer resistant to hormone therapy. Despite initial success, everolimus has not yet realized its full therapeutic potential due to its associated toxicities and the development of resistance. Here, we exploited biocompatible lignin nanoparticles to enhance everolimus delivery and the mechanism of action in hormone receptor-positive breast cancer cells. Everolimus was released from the lignin nanoparticles in a concentration-dependent manner, following a Fickian diffusion-like model. The nanoparticles protected the drug from potential pH-induced degradation. Confocal microscopy confirmed the diffusion and cytoplasmic localization of lignin nanoparticles, as well as the efficient release of the drug. Everolimus release effectively inhibits the proliferation in breast cancer MCF7 cells. EVE/LNPs showed an improved in vitro antitumor effect compared to EVE against the MCF7 cell line (63 vs 81% survival rate at 10 nM). Under acidic pH conditions, the lignin nanoparticles underwent partial degradation, probably generating oligomers with potential modulating effects on mTOR and FOXM1. Molecular docking simulations showed that lignin oligomers could selectively interact with the ATP-binding cavity of mTOR. The affinity of these interactions was modulated by the redox state of the lignin oligomers, with the strongest bond being observed for quinone derivatives. This dual-action mechanism, which combines drug delivery and modulation of cellular signaling, offers a promising "on/off" switch approach to enhance everolimus-based cancer therapies. Further in vivo studies are warranted to validate these findings.