Reduction/Oxidation-Responsive Hierarchical Nanoparticles with Self-Driven Degradability for Enhanced Tumor Penetration and Precise Chemotherapy.

Deep tumor penetration and long blood circulation, rapid drug release and sufficient stability are the two most concerned dilemmas of nano drug delivery systems for efficient chemotherapy. Herein, we develop a reduction/oxidation- responsive hierarchical nanoparticles coencapsulating paclitaxel (PTX) and pH-stimulated hyaluronidase (pSH) to surmount the sequential biological barriers for precise cancer therapy. Poly(ethylene glycol) diamine (PEG-dia) is applied to collaboratively crosslink the shell of nanoparticles self-assembled by a hyaluronic acid-stearic acid conjugate linked via a disulfide-bond (HA-SS-SA, HSS) to fabricate the hierarchical nanoparticles (PHSS). The PTX and pSH co-loaded hierarchical nanoparticles (PTX/pSH-PHSS) enhance the stability in normal physiological conditions and accelerate drug release at tumorous pH, high reductive or oxydic environments. Functionalized with PEG and HA, the hierarchical nanoparticles preferentially prolong the circulation time, accumulate at the tumor site and enter MDA-MB-231 cells via CD44-mediated endocytosis. Within the acidic tumor microenvironment (TME), pSH would be partially reactivated to decompose the dense tumor extracellular matrix (ECM) for deep tumor penetration. Interestingly, PTX/pSH-PHSS could be degraded apace by the completely activated pSH within endo/lysosomes and the intracellular redox microenvironment to facilitate drug release to produce the highest tumor inhibition (93.71%) in breast cancer models.