Bioinspired Tumor‐Targeting and Biomarker‐Activatable Cell‐Material Interfacing System Enhances Osteosarcoma Treatment via Biomineralization

Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor‐targeting and enzyme‐activatable cell‐material interface system based on DDDEEK‐pY‐phenylboronic acid (SAP‐pY‐PBA) conjugates. Using this tandem‐activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP‐pY‐PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme‐responsive biointerface combining supramolecular hydrogels with biomineralization.