Physalis Mottle Virus-Like Nanocarriers with Expanded Internal Loading Capacity

by Selleckchem | Nov 10 2023

An ongoing challenge in precision medicine is the efficient delivery of therapeutics to tissues/organs of interest. Nanoparticle delivery systems have the potential to overcome traditional limitations of drug and gene delivery through improved pharmacokinetics, tissue targeting, and stability of encapsulated cargo. Physalis mottle virus (PhMV)-like nanoparticles are a promising nanocarrier platform which can be chemically targeted on the exterior and interior surfaces through reactive amino acids. Cargo-loading to the internal cavity is achieved with thiol-reactive small molecules. However, the internal loading capacity of these nanoparticles is limited by the presence of a single reactive cysteine (C75) per coat protein with low inherent reactivity. Here, we use structure-based design to engineer cysteine-added mutants of PhMV VLPs that display increased reactivity toward thiol-reactive small molecules. Specifically, the A31C and S137C mutants show a greater than 10-fold increased rate of reactivity towards thiol-reactive small molecules, and PhMV Cys1 (A31C), PhMV Cys2 (S137C), and PhMV Cys1+2 (double mutant) VLPs display up to three-fold increased internal loading of the small molecule chemotherapeutics aldoxorubicin and vcMMAE and up to four-fold increased internal loading of the MRI imaging reagent DOTA(Gd). These results further improve upon a promising plant virus-based nanocarrier system for use in targeted delivery of small-molecule drugs and imaging reagents in vivo.

Comments:

The use of nanocarrier systems like Physalis mottle virus (PhMV)-like nanoparticles for precision medicine is indeed an exciting and promising field of research. Your description highlights some key advancements in this area, particularly in engineering cysteine-added mutants of PhMV VLPs to improve their reactivity and cargo-loading capacity. Here are some key points to consider:

1. **Improved Cargo Loading**: The modification of PhMV VLPs to include additional reactive cysteine residues (A31C and S137C mutants) has significantly enhanced their ability to load thiol-reactive small molecules. This is crucial for efficient drug and imaging agent delivery, as it allows for higher payload capacity.

2. **Targeted Drug Delivery**: These modified PhMV VLPs can serve as excellent carriers for small-molecule chemotherapeutics like aldoxorubicin and vcMMAE. This targeted delivery approach can potentially minimize off-target effects and improve the therapeutic index of these drugs.

3. **Enhanced Imaging Capabilities**: The ability to load DOTA(Gd) as an MRI imaging reagent is a valuable application of these engineered nanoparticles. Improved loading capacity (up to four-fold) makes them more effective as contrast agents for imaging, which can aid in diagnostics and monitoring treatment responses.

4. **Structure-Based Design**: The approach of using structure-based design to engineer these VLPs is a sophisticated and rational method. It demonstrates the importance of understanding the structural aspects of nanocarriers to optimize their properties for drug and imaging agent delivery.

5. **Potential for In Vivo Applications**: The enhanced loading capacity and reactivity of these engineered PhMV VLPs make them attractive candidates for in vivo applications. Their ability to target specific tissues/organs and deliver payloads efficiently can potentially improve the effectiveness of therapies and reduce side effects.

6. **Future Directions**: Further research may focus on fine-tuning these engineered VLPs, optimizing their pharmacokinetics, and conducting preclinical studies to evaluate their safety and efficacy in animal models. Additionally, exploring ways to functionalize their exteriors for even more precise targeting could be a valuable avenue of research.

In summary, the development of engineered PhMV-like nanoparticles with increased reactivity and cargo-loading capacity represents a significant advancement in the field of precision medicine. This technology has the potential to revolutionize drug and imaging agent delivery, offering new possibilities for more effective and targeted treatments.