Ferroptosis/Apoptosis Induction by an Iridium Complex Encapsulated in PLGA Nanoparticles Enhances Efficacy and Reduces Toxicity in Breast Cancer

Conventional chemotherapy faces systemic toxicity and suboptimal efficacy, necessitating innovative strategies. Herein, three iridium(III) complexes (PIQ, PPY, and BZQ) were synthesized, and PPY exhibited remarkable cytotoxicity against breast cancer cells (IC₅₀ = 2.08 μM) by coinducing apoptosis/ferroptosis. Mechanistically, this dual effect is mediated via ROS overproduction, mitochondrial dysfunction, PI3K/AKT/mTOR signaling pathway inhibition, and GPX4 suppression, which collectively augment lipid peroxidation. Encapsulating PPY into biodegradable PLGA nanoparticles (PPY-NPs) enhanced tumor-specific delivery, achieving 78% tumor growth inhibition in mice with attenuated systemic toxicity. Pharmacokinetic studies revealed that PPY-NPs had reduced <i>AUC</i>, comparable to <i>MRT</i>, accelerated <i>Cl</i>, and increased <i>V</i>_d compared to free PPY, consistent with MPS-mediated clearance. Collectively, this approach harnesses the multitarget activity of iridium coupled with nanocarrier-enabled spatiotemporal control, overcoming bioavailability limitations and amplifying tumor-specific oxidative stress. By simultaneously activating apoptosis and ferroptosis, PPY-NPs overcome the limitations of conventional agents' single-pathway therapeutic approaches, offering an expanded mechanistic therapeutic paradigm.