1334 Employing bioengineered virus-like particles: innovative strategies for targeting tumors, suppressing growth, and preventing metastasis

<h3>Background</h3> Targeted therapy using engineered fusion proteins, antibodies, or peptides is an efficient and promising approach to reduce the toxicity associated with cancer therapeutics. Among the most promising therapies, it offers advantages such as effectively targeting the site of action and minimizing off-target effects. Monoclonal antibodies have emerged as useful therapeutic agents, but they are associated with instability, toxicity, rapid clearance, drug resistance, and high production costs. Emerging research focuses on bioengineering virus-like particles (VLPs) because they offer various sites for modification and can mimic viral structures. They possess unique characteristics such as good cell penetration, scalable production, and efficient cargo carriage. Genetic modification of VLPs allows for the expression of entire coding sequences, enabling the production of short peptides and full proteins for safe and efficient delivery to various sites. Depending on the insertion site, such as the N- or C-terminus, their expression can be utilized on the surface or inside the capsid. Bioengineered VLPs have long been used as therapeutics against cancer. This project aims to target tumors overexpressing HER2 and PDL1 genes using genetically modified VLPs with exterior receptors that exhibit high affinity for these genes. The modified VLPs, approximately 30 nm in size, are sufficiently large to inhibit tumor growth by blocking growth signals. Additionally, the interior of these VLPs will contain packed RNA to silence specific tumor-promoting genes that affect cell proliferation and tumor progression. This single-tool therapy aims to target tumors, arrest their growth, and deliver single-stranded RNA to silence genes for tumor eradication. <h3>Methods</h3> This expression system is achieved using a dual-plasmid system. The first plasmid consists of a pCDF vector containing coat proteins (CP) and the RNA sequence under a T7 promoter. The other plasmid was constructed using a pBAD vector containing the HER2 or PDL1 receptor sequence linked with a linker to the CP sequence. <h3>Results</h3> We have demonstrated high targeting affinity towards the HER2 and PDL1 genes using Surface Plasmon Resonance (SPR). Biodistribution studies <i>in-vivo</i> indicated specific tumor targeting following intravenous administration, without off-targeting issues. Our tool effectively inhibited tumor growth in mouse models. <h3>Conclusions</h3> In summary, we have shown that modified VLPs can effectively target and inhibit tumor growth in HER2 models <i>in-vivo</i> (figure 1). Our ongoing objective is to further demonstrate tumor suppression and the prevention of metastasis using single stranded RNA (siRNA) technology.