Dual-Responsive and Deep-Penetrating Nanomicelles for Tumor Therapy via Extracellular Matrix Degradation and Oxidative Stress

Tumor microenvironment (TME), with complex composition, plays a vital role in the occurrence, development, and metastasis of tumors. TME becomes an important obstacle to the accessibility of nanotherapy, thus indicating the need to improve the functional design to overcome this challenge. In this study, we generate an intelligent nano-drug-delivery system (DOX@PssP-Hh NPs) with dual environmental response, which involves heparanase (HPSE) in TME and glutathione (GSH) in tumor cells. The nanosystem consists of a nanoskeleton formed by self-assembly of mPEG-ss-PEI and α-CD (PssP), chemotherapy drug doxorubicin (DOX) for enhancing antitumor efficacy, together with hyaluronidase (HAase), which is designed to degrade extracellular matrix to increase drug penetration, and an outer shell of heparin. Through the process of “responsive disintegration–remodeling tumor microenvironment–enhancing drug penetration–inducing oxidative stress”, the semi-rotaxaneself-assembled nanomicelles were constructed to achieve the progressive function. DOX@PssP-Hh NPs with the size of 81.85 ± 1.85 nm exhibited satisfactory cytotoxicity (IC50= 0.80 ± 0.33 μg/mL). With the disulfide bond-mediated GSH depletion and DOX-mediated reactive oxygen species (ROS) production, treatment with DOX@PssP-Hh NPs prominently reduced glutathione peroxidase 4 (GPX4) level and would lead to enhanced oxidative stresses. Hyaluronic acid (HA), collagen I, and α-smooth muscle actin (α-SMA) were significantly reduced for TME remodulation. Moreover, the antitumor effect in vivo implied that DOX@PssP-Hh NPs could inhibit tumor growth effectively and reduce tumor interstitial fluid pressure (IFP) evidently. In conclusion, DOX@PssP-Hh NPs improved the penetration of drugs and exhibited enhanced antitumor efficacy.