Intelligent Size‐Switchable Iron Carbide‐Based Nanocapsules with Cascade Delivery Capacity for Hyperthermia‐Enhanced Deep Tumor Ferroptosis

Abstract The ferroptosis pathway is recognized as an essential strategy for tumor treatment. However, killing tumor cells in deep tumor regions with ferroptosis agents is still challenging because of distinct size requirements for intratumoral accumulation and deep tumor penetration. Herein, intelligent nanocapsules with size‐switchable capability that responds to acid/hyperthermia stimulation to achieve deep tumor ferroptosis are developed. These nanocapsules are constructed using poly(lactic‐co‐glycolic) acid and Pluronic F127 as carrier materials, with Au–Fe₂C Janus nanoparticles serving as photothermal and ferroptosis agents, and sorafenib (SRF) as the ferroptosis enhancer. The PFP@Au–Fe₂C–SRF nanocapsules, designed with an appropriate size, exhibit superior intratumoral accumulation compared to free Au–Fe₂C nanoparticles, as evidenced by photoacoustic and magnetic resonance imaging. These nanocapsules can degrade within the acidic tumor microenvironment when subjected to laser irradiation, releasing free Au–Fe₂C nanoparticles. This enables them to penetrate deep into tumor regions and disrupt intracellular redox balance. Under the guidance of imaging, these PFP@Au–Fe₂C–SRF nanocapsules effectively inhibit tumor growth when exposed to laser irradiation, capitalizing on the synergistic photothermal and ferroptosis effects. This study presents an intelligent formulation based on iron carbide for achieving deep tumor ferroptosis through size‐switchable cascade delivery, thereby advancing the comprehension of ferroptosis in the context of tumor theranostics.