Orchestrated Molecularly Imprinted Nanoparticles for Tumor-Targeted and Chemo-Photothermal Therapy

Effective eradication of cancer cells while minimizing damage to normal tissues remains a significant challenge in clinical oncology. Herein, a multifunctional nanoplatform (DFD-MIP) was developed through sequential fabrication of a doxorubicin (DOX)-loaded inner layer and a P32 epitope-imprinted outer layer on Fe₃O₄ nanoparticles (NPs), using dopamine as both functional monomer and cross-linker. To assess therapeutic superiority of DFD-MIP, comprehensive in vitro and in vivo studies were conducted. Results demonstrated that the epitope-imprinted outer layer served both as an artificial antibody for P32 overexpressed tumor cell recognition and as a "gatekeeper" to prevent drug leakage during circulation, thereby reducing systemic toxicity. Upon cellular internalization, the acidic tumor microenvironment triggered the sequential degradation of polydopamine (PDA)-based layers, enabling pH-responsive DOX release directly within tumor cells. Synergistically, under 808 nm near-infrared irradiation, the combined photothermal conversion capabilities of Fe₃O₄ NPs and PDA residues generated enhanced hyperthermia. This chemo-photothermal combination therapy achieved superior tumor suppression through localized drug activation and thermal ablation of residual cancer cells. DFD-MIP integrated multiple desirable features including simplified composition, active targeting capability, excellent biocompatibility, prolonged tumor retention, and pH-responsive drug release. This platform significantly improves chemotherapeutic drug bioavailability while reducing off-target effects, providing a prototype for the development of multifunctional targeted drug delivery systems.