Lung Metastasis-Targeted Donut-Shaped Nanostructures Shuttled by the Margination Effect for PolyDox Generation-Mediated Penetrative Delivery into Deep Tumors
An octopus-like donut that can effectively approach the lung metastasis and offer burst penetrative delivery to overcome tumor heterogeneity is proposed. The intravenously injected donut serves as a tumor-adhesion agent through the margination effect and hierarchical octopus-like structure, which drives nanoparticle-induced extracellular leakiness (nanoEL) both in vitro and in vivo. In an animal metastasis model, more than 72% of donuts localize to lung metastatic tumors instead of to normal tissues. Upon application of a high-frequency magnetic field (MF), a burst generation of polydox (pDox) particles from the carbon porous reservoirs of donuts enhance the retention in deep tumor, facilitating penetrative delivery. Via pH-responsive hydrozone bonds, the penetrative pDox particles are cleaved into doxorubincin (Dox), yielding high intracellular concentrations of activated Dox at tumor. The octopus-like donut loaded with pDox improved the survival rates in a mouse model of metastatic lung cancer and the activity of immune response.