Magnetically Actuated Active Deep Tumor Penetration of Deformable Large Nanocarriers for Enhanced Cancer Therapy

Abstract The intrinsic pathological microenvironment of tumor tissue enforces barriers to the passive diffusion of nanomedicine, which results in inefficient tumor penetration of drugs and unsatisfactory therapeutic efficacy. Various strategies have been developed to improve the tumor penetration of nanomedicine, but they mostly overcome the barriers separately at different steps in a passive diffusion process. Here, the development of a large polymeric nanocarrier, DA T‐PPE D&F (≈180 nm), is reported, which comprises a flowable polyphosphoester core, ferrimagnetic nanocubes, and a tumor extracellular pH‐sensitive transactivator of transcription (TAT). Compared with a polylactic acid‐based nanocarrier with a rigid core, this deformable DA T‐PPE D&F with a similar diameter exhibits efficient penetration into the deep tumor tissue under magnetic actuation and an enhanced reactivation rate of the pH e ‐sensitive TAT. Therefore, DA T‐PPE D&F is able to efficiently deliver doxorubicin into most tumor cells in vivo, and the superior anticancer effect indicates the potential of DA T‐PPE D&F as a universal, responsive, and active nanocarrier to deliver various hydrophobic drugs into the deep tumor tissue.