Toll-like receptor (TLR) 7/8 agonists, such as imidazoquinoline derivatives (IMDs), hold great potential as immune modulators that can boost innate antiviral and anticancer immunity. However, significant challenges persist in achieving sufficient efficacy while minimizing toxic side effects. To date, only imiquimod (IMQ) has received FDA approval, and its use is restricted to topical applications. Therefore, there is a significant need for novel and safe TLR 7/8 agonists. In response to this, we developed a new generation of TLR7/8 agonist, the PapMV nanoparticle (PapMV nano). IMDs and PapMV nano are both innate immune system-activating drugs that have demonstrated antiviral and anticancer activities, but they differ significantly in three key aspects: (1) composition (proteins and ssRNA for PapMV nano vs. synthetic molecules for IMDs), (2) structure (large nanoparticles vs. small molecules), and (3) the mechanism of cell entry (internalization for PapMV nano vs. cell diffusion for IMDs). To compare how immune cells react to these two types of drug products, we studied cell motility, cell metabolism, and the induction of apoptosis in human monocyte-derived macrophages (hMDMs). Our data reveal that PapMV nano enhances motility and mitochondrial respiration while decreasing glycolysis, whereas IMDs have no impact on motility and mitochondrial respiration but increase glycolysis. PapMV nano is also the only agonist that does not induce apoptosis. Although the cellular responses to these two types of agonists differ strikingly, both are capable of eliciting antiviral immunity. We confirmed this potential for PapMV nano by demonstrating its capacity to prevent SARS-CoV-2 infection, supporting its utilization as a safe and effective immune modulator, capable of providing broad protection against respiratory viruses.
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