Tumor Microenvironment‐Triggered Charge‐Reversible Molecularly Imprinted Polymers for Dual Cascade Targeting to Enhance Photothermal Therapy

Mitochondrion, a key subcellular organelle, acts as the cell's energy supplier and metabolic regulator. Given its vital functions and distinct thermal sensitivity, it's a suitable target for tumor photothermal therapy (PTT). However, current mitochondrial targeting agents are easily cleared during in vivo circulation and may non-specifically target normal cells. Herein, to address these issues, a novel cascade-targeting molecularly imprinted polymer (MIP) with charge-reversal capability was constructed, avoiding exogenous ligand modification. During MIP synthesis, Fe3O4 modified with (3-carboxypropyl)triphenylphosphonium bromide was used as the carrier to provide photothermal effect and mitochondrial targeting. Furthermore, incorporating 2-methacryloyloxyethyl phosphorylcholine boosted the imprinting factor and endowed charge reversal, enabling specific, stealthy tumor targeting and enhanced cellular internalization under weak acidity. Following intracellular entry, glutathione-mediated degradation of the reductive cross-linker released the carrier for second-stage mitochondrial targeting. Thereafter, under 808 nm laser irradiation, Fe3O4 exerted a robust photothermal effect. Cellular uptake and mitochondrial colocalization confirmed cascade targeting capability, while in vitro tumor spheroid penetration demonstrated charge-reversal MIP facilitated more efficient internalization. In vivo experiments revealed MIP exhibited the strongest anti-tumor efficacy under irradiation. This work fully leveraged the designability of MIP, integrating charge reversal with cascade targeting functionalities, and provided a novel strategy for improving PTT.