Endogenous Fe2+-triggered self-targeting nanomicelles for self-amplifying intracellular oxidative stress

Abstract

Background: Artesunate (ASA) acts as an •O₂^- source through the breakdown of endoperoxide bridges catalyzed by Fe²⁺, yet its efficacy in ASA-based nanodrugs is limited by poor intracellular delivery.

Methods: ASA-hyaluronic acid (HA) conjugates were formed from hydrophobic ASA and hydrophilic HA by an esterification reaction first, and then self-targeting nanomicelles (NM) were developed using the fact that the amphiphilic conjugates of ASA and HA are capable of self-assembling in aqueous environments.

Results: These ASA-HA NMs utilize CD44 receptor-mediated transcytosis to greatly enhance uptake by breast cancer cells. Subsequently, endogenous Fe²⁺ from the tumor catalyzes the released ASA to produce highly toxic •O₂^- radicals to kill tumor cells, although sustained tumor growth inhibition can be achieved via in vivo experiments.

Conclusions: Self-targeting NMs represent a promising strategy for enhancing ASA-based treatments, leveraging clinically approved drugs to expedite drug development and clinical research in oncology.

Keywords: nanomicelles; non‐Fenton; oxidative stress; reactive oxygen species; self‐targeting.