Over the past two decades, the "protein corona" concept has guided research into nanoparticle protein interactions, yet most studies have focused on nonspecific adsorption determined mainly by physicochemical properties of nanomaterials. Whether nanomaterials can specifically recognize proteins and the mechanisms underlying such selectivity remain largely unknown.

In a study published in Exploration, a research team led by Prof. LI Yang from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences revealed how black phosphorus nanomaterials (BPNMs) recognize and bind a key cell cycle regulator, polo like kinase 1 (PLK1).

Researchers found that BPNMs uniquely and selectively interact with PLK1, while showing little or no affinity for other members of the PLK family. This selective binding caused PLK1 molecules to aggregate, suppressed their enzymatic activity, and interfered with the division of cancer cells.

Using nanobiological, biochemical and computational simulation approaches, researchers systematically analyzed how BPNMs interact with five homologous PLK proteins (PLK1 to PLK5). They found that the strong preference for PLK1 arose from its distinctive physicochemical features including its positively charged surface regions, hydrophobic patches, and tightly folded secondary structure.

Structural mapping showed that BPNMs interacted simultaneously with two key functional domains of PLK1, the kinase domain responsible for enzyme activation and the polo box domain that controls protein degradation. By targeting both domains, BPNMs blocked PLK1 activation and degradation, leading to complete inhibition of its function in cell cycle regulation.

To overcome issues of the instability and oxidation sensitivity of black phosphorus, researchers developed cell membrane coated BPNMs which show greatly improved stability, prolonged circulation, and enhanced tumor targeting. In animal models, these biomimetic nanomaterials achieved enhanced antitumor efficacy and excellent biocompatibility after systemic administration.

Understanding how nanomaterials interact with biological macromolecules is essential for advancing nanomedicine. This study introduces the concept of "mutual selection" between nanomaterials and proteins, showing that their interactions are jointly defined by the physicochemical properties of both sides. It establishes a theoretical foundation for the rational design of targeted, safe, and effective nanomedicines.