pH-Sensitive Biomimetic Nanosystem Based on Large-Pore Mesoporous Silica Nanoparticles with High Hyaluronidase Loading for Tumor Deep Penetration

Loadinghyaluronidase (Hyal) in a nanocarrier is a potent strategyto degrade the tumor extracellular matrix for tumor deep penetrationand enhanced tumor therapy. Herein, a pH-sensitive biomimicking nanosystemwith high Hyal loading, effective tumor targeting, and controllablerelease is constructed. Specifically, cationic mesoporous silica nanoparticles(CMSNs) with large pores 13.52 nm in diameter were synthesized ina one-pot manner by adding N-[3-trimethoxysilylpropyl]-N,N,N-trimethylammoniumto a reversed microemulsion reaction system. The Hyal loading ratewas as high as 19.47% owing to matched pore size and the cationicsurface charge. Subsequently, a pH-sensitive biomimetic hybrid membrane(pHH) composed of pH-sensitive liposome (pHL), red blood cell membrane,and pancreatic cancer cell membrane was camouflaged on the pHL-coatedand doxorubicin/Hyal-loaded CMSNs (shortened as DHCM). The DHCM@pHL@pHHis stable at neutral pH while it releases the payloads smoothly inthe tumor acidic microenvironment. Consequently, it can escape frommacrophage clearance, be specifically taken up by pancreatic cancercells, and efficiently accumulate at the tumor site. More importantly,it can penetrate deeply in pancreatic tumors with a tumor growth inhibitionratio of 80.46%. The nanosystem is biocompatible and has potentialfor clinical transformation, and the nanocarrier is promisingly applicableas a platform for encapsulation of various macromolecules for smartand tumor-targeted delivery.

Automated summary

In this study, a pH-sensitive biomimicking nanosystem with high hyaluronidase loading, effective tumor targeting, and controllable release was constructed. This nanosystem can degrade the tumor extracellular matrix, penetrate deeply into the tumor, and enhance tumor therapy.