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.
Melittin, the principal constituent in bee venom, is an attractive candidate for cancer therapy. However, its clinical applications are limited by hemolysis, nonspecific cytotoxicity, and rapid metabolism. Herein, a novel genetically engineered vesicular antibody‐melittin (VAM) drug delivery platform was proposed and validated for targeted cancer combination therapy. VAM generated from the cellular plasma membrane was bio‐synthetically fabricated, with the recombinant protein (hGC33 scFv‐melittin) being harbored and displayed on the cell membrane. The bioactive and targetable nanomelittin conjugated by hGC33 scFv could be released in an MMP14‐responsive manner at tumor sites, which reduced off‐target toxicity, especially the hemolytic activity of melittin. Importantly, VAM could be loaded with small‐molecule drugs or nanoparticles for combination therapy. Nanomelittin formed pores in membranes and disturbed phospholipid bilayers, which allowed the anticancer agents (i.e., chemotherapeutic drug doxorubicin and sonosensitizer purpurin 18 nanoparticles) co‐delivered by VAM to penetrate deeper tumor sites, leading to synergistic therapeutic effects. In particular, the punching effect generated by sonodynamic therapy further improved the immunomodulatory effect of nanomelittin to activate the immune response. Taken together, our findings indicate that clinically translatable VAM‐based strategies represent a universal, promising approach to multimodal synergetic cancer therapy.
Vaccination is the most cost-effective means in the fight against infectious diseases. Various kinds of vaccines have been developed since the outbreak of COVID-19, some of which have been approved for clinical application. Though vaccines available achieved partial success in protecting vaccinated subjects from infection or hospitalization, numerous efforts are still needed to end the global pandemic, especially in the case of emerging new variants. Safe and efficient vaccines are the key elements to stop the pandemic from attacking the world now; novel and evolving vaccine technologies are urged in the course of fighting (re)-emerging infectious diseases. Advances in biotechnology offered the progress of vaccinology in the past few years, and lots of innovative approaches have been applied to the vaccine design during the ongoing pandemic. In this review, we summarize the state-of-the-art vaccine strategies involved in controlling the transmission of SARS-CoV-2 and its variants. In addition, challenges and future directions for rational vaccine design are discussed.
Upon harnessing low-intensity ultrasound to activate sonosensitizers, sonodynamic therapy (SDT) induces cancer cell death through the reactive oxygen species (ROS) mediated pathway. Compared with photodynamic therapy (PDT), SDT possesses numerous advantages, including deeper tissue penetration, higher accuracy, fewer side effects, and better patient compliance. Sinoporphyrin sodium (DVDMS), a sonosensitizer approved by the FDA, has drawn abundant attention in clinical research, but there are some deficiencies. In order to further improve the efficiency of DVDMS, many studies have applied self-assembly nanotechnology to modify it. Furthermore, the combined applications of SDT/chemodynamic therapy (CDT) have become a research hotspot in tumor therapy. Therefore, we explored the self-assembly of nanoparticles based on DVDMS and copper to combine SDT and CDT. A cost-effective sonosensitizer was synthesized by dropping CuCl2 into the DVDMS solution with the assistance of PVP. The results revealed that the nanostructures could exert excellent treatment effects on tumor therapy and perform well for PET imaging, indicating the potential for cancer theranostics. In vitro and in vivo experiments showed that the nanoparticles have outstanding biocompatibility, higher ROS production efficiency, and antitumor efficacy. We believe this design can represent a simple approach to combining SDT and CDT with potential applications in clinical treatment and PET imaging.
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