Natural mussel protein-derived antitumor nanomedicine with tumor-targeted bioadhesion and penetration

Increasing drug infiltration by exerting tumor-specific retention and penetration is a key aspect for antitumor nanomedicine design. Herein, we have developed a mussel adhesive protein-inspired nanomedicine with tumor-targeted adhesion and penetration for enhanced photodynamic therapy and hypoxia-driven chemotherapy. Natural mussel adhesive proteins (NMPs) are conjugated to phenylboronic acid (PBA)-containing Tirapazamine prodrug (PBT) via recognization of DOPA residues of NMPs to PBA moieties of PBT, endowing NMPs with tumor environment-responsive bioadhesion while unaffecting their systematic circulation. Indocyanine green (ICG) is further incorporated into NMPs to acquire nanomedicine [email protected] with reduced cationic property. In the tumor environment, the cationic property is upturned with the responsive cleavage of DOPA-PBA bonding, facilitating tumor penetration. [email protected] are then internalized by tumor cells through arginine-transporter endocytosis. Triggered by near-infrared irradiation, [email protected] generate cytotoxic reactive oxygen species and aggravate tumor hypoxia, which potentiates PBT activation, therefore showing combination antitumor effect in both orthotopic and metastatic breast tumor models.