A Slimming/Excavating Strategy for Enhanced Intratumoral Penetration of Acid‐Disassemblable NO‐Releasing Nanomedicines

Poor tumor penetration is the major predicament of nanomedicines that limits their anticancer efficacy. The dense extracellular matrix (ECM) in the tumor is one of the major barriers against the deep penetration of nanomedicines. In this work, a slimming/excavating strategy is proposed for enhanced intratumoral penetration based on an acid-disassemblable nanomicelles-assembled nanomedicine and the NO-mediated degradation of ECM. The nanomedicine is constructed by cross-linking nanomicelles, which are self-assembled with two kinds of dendrimers containing phenylboronic acid and lactobionic acid, through borate esterification. In the acidic tumor microenvironment, the pH-sensitive borate ester bonds among the nanomicelles are hydrolyzed, triggering the disassembly of nanomedicine (≈150 nm) into small nanomicelles (≈25 nm). In response to the intratumoral over-expressed glutathione (GSH), the NO donor loaded in the nanomicelles produces NO, which mediates the expression of matrix metalloproteinases for the degradation of ECM in the tumor. By collaboration of the disassembling behavior of nanomedicine with the NO-mediated degradation of ECM, the designed nanomedicine can penetrate a long distance in tumors. The proposed slimming/excavating strategy will provide inspiration for overcoming the challenge of nanomedicines in tumor penetration.