Genetically Engineered Nanohyaluronidase Vesicles: A Smart Sonotheranostic Platform for Enhancing Cargo Penetration of Solid Tumors

Abstract

Precise anti‐cancer therapy is hampered by aberrant tumor microenvironments (TME), which include the important features of the dense tumor extracellular matrix (ECM) and hypoxia. The capability of hyaluronidase (HAase) to degrade hyaluronic acid (HA), the main component of ECM, can prompt its rapid development in sonotherapeutics aimed at regulating the microenvironment. In this study, the authors design a bioengineering‐based smart enzymatic nanovesicle mHAase combined with purpurin 18 (P18) to form mHAase@nP18 that naturally anchors native HAase to the matrix metalloproteinase‐2 (MMP‐2) cleavable peptide. This nanovesicle system demonstrates a high expression of HAase and drug loading capability of the sonosensitizer, purpurin 18, for dual‐mode fluorescence/photoacoustic imaging‐guided sonodynamic therapy (SDT). Notably, mHAase@nP18 shows enhanced enzyme stability and activity in comparison to free HAase owing to avoidance of the protein crown shield; meanwhile, the released HAase causes a further elevation of its activity for SDT in an MMP‐2‐dependent manner. In vitro and in vivo results indicate the mHAase@nP18 can greatly enhance tumor penetration and alleviate hypoxia via HA degradation, further causing a heightened SDT effect. This work provides a promising strategy of stimuli‐responsive bioengineering of cell membrane vesicles for effective TME modulation and enhanced therapeutic results.

Genetically Engineered‐Cell‐Membrane Nanovesicles for Cancer Immunotherapy

“…Compared with other groups, mHAase + MMP‐2 had the highest uptake in HepG2 cells, further indicating that mHAase + MMP‐2 damaged the ECM and played an important role in enhancing drug uptake in tumor cells (Figure 10G). [ 92 ] HAase cannot be expressed through gene modification in nonnucleated cells such as red blood cells; therefore, to modify HAase on the surface of red blood cells, chemical modification can be adopted. For example, Cheng and co‐workers chemically modified human recombinant hyaluronidase PH20 on red blood cell membranes and extracted the membrane coated with NPs to prepare a drug delivery system.…”

Cell membrane‐coated nanoparticles for the treatment of bacterial infection

“…Furthermore, genetically engineered cell membranes can be used to confer functions that are not possessed by source cells (Ren et al, 2021). Genetically engineered cell membranes have been reported in tumor therapy (Chen et al, 2022; X. Liu, Liu, et al, 2019; Lv et al, 2019; Xu et al, 2022), diagnostics (Ren et al, 2020), autoimmune disease (Shi et al, 2020), antiviral (Xuan et al, 2018; P. Zhang, Chen, et al, 2015; P. Zhang, Liu, & Chen, 2017), and antibacterial infections (Pang, Liu, et al, 2019). Inspired by these approaches, in the future, multiple antimicrobial elements can be simultaneously expressed on cell membranes to integrate into a multifunctional cell membrane for the treatment of bacterial infection.…”

Enzyme-Triggered Size-Switchable Nanosystem for Deep Tumor Penetration and Hydrogen Therapy

“…Drug delivery nanocarriers hold great promise for the fight against cancers by increasing drug bioavailability and drug tumor accumulation. − Nevertheless, limited tumor penetration is currently recognized as a major hindrance for nanomedicines to achieve satisfactory therapeutic outcomes, which may even lead to tumor regeneration or metastasis. − The poor intratumor diffusion of nanomedicines is primarily attributed to the several physiological barriers of the solid tumor microenvironment, which includes dense extracellular matrices (ECM), − elevated interstitial fluid pressure (IFP) , and disorganized vasculature. , To address the penetration problem, several strategies have been exploited, such as proteolytic enzyme decoration, − penetrating peptide modification, − vasculature normalization , and particle size control. , Despite advances for facilitating nanoparticle penetration into tumor tissue, these strategies are accompanied by adverse effects that may limit their practical application. For instance, enzymes are labile entities that easily suffer from a rapid degradation in living tissues due to proteases or other aggressive agents in the bloodstream. , Besides, enzyme digestion of ECM components may lead to the undesirable risk of tumor progression and metastasis. , Penetrating peptides have nonspecificity , and are easily scavenged by the reticuloendothelial system .…”