Robust Cu²⁺-Modified Black Phosphorus Nanoplatform for Enhanced Drug Delivery and Synergistic Multimodal Tumor Therapy via Metal Ion-Assisted π–π Interactions

The application of 2D nanomaterials for drug delivery via π–π interactions has been extensively investigated. However, these interactions often lack robustness in the presence of blood proteins due to the competitive binding of blood proteins, which results from strong π–π-stacking interactions with aromatic protein residues. This can lead to premature drug release and diminished therapeutic efficacy. To address this challenge, we developed a robust 2D delivery/therapeutic biomimetic nanoplatform that enhances the adsorption affinity and targeted delivery efficiency of the chemotherapeutic drug doxorubicin (DOX) by utilizing Cu²⁺-modified black phosphorus nanosheets (BP@Cu²⁺) through metal ion-assisted π–π interactions. The synergistic interactions between the π-electrons of BP and DOX, mediated by Cu²⁺ coordination, form a stable sandwiched π-cation-π stacking complex (BP@Cu²⁺/DOX). This metal-ion-bridged architecture significantly enhances the DOX loading capacity and minimizes premature release in serum. In the acidic tumor microenvironment, this interaction is disrupted, enabling controlled release of both DOX and Cu²⁺ ions. Furthermore, the encapsulation of the complex within tumor cell membranes significantly enhances the efficiency of tumor targeting, resulting in a biomimetic nanoplatform (BP@Cu²⁺/DOX-CMs). Combined with near-infrared laser irradiation, this nanoplatform achieves synergistic multimodal therapy by integrating phototherapy, chemotherapy, chemodynamic therapy, and cuproptosis to enhance antitumor efficacy. The study highlights the potential of metal ion-assisted π–π stacking interactions in the development of advanced 2D nanoplatforms, thereby paving the way for innovative biomedical applications utilizing conventional 2D nanomaterials.