# Evaluating the Antiviral Efficacy of Encapsulated PKC Inhibitor BIM‐I against influenza A Virus Infection

## TL;DR

This study shows that encapsulating a PKC inhibitor called BIM-I in nanoparticles improves its safety and effectiveness against influenza A virus, with promising results using a PEG alternative for nanoparticle coatings.

## Contribution

The study introduces a novel nanoparticle delivery system for BIM-I that improves its antiviral efficacy and safety, and proposes PEtOx as a viable alternative to PEG in nanomedicine.

## Key findings

- Encapsulation of BIM-I in PLGA nanoparticles improved its cellular tolerability without reducing antiviral activity.
- Surface modification with PEtOx showed efficient nanoparticle uptake and could replace PEG in nanomedicine.
- Confocal microscopy confirmed effective cellular uptake of PEGylated and PEtOxylated BIM-I nanoparticles.

## Abstract

Influenza A virus (IAV) infections remain a major global health threat, as current vaccines and antivirals often lose efficacy due to frequent viral mutation and resistance development. This underscores the urgent need for novel therapeutic strategies, such as targeting host factors, which may reduce the likelihood of resistance. Here, we evaluated inhibitors of G protein‐coupled receptor kinases (GRKs; paroxetine, CMPD101) and protein kinase C (PKC; Gö6983, bisindolylmaleimide‐I (BIM‐I)) for anti‐IAV activity. GRK inhibition showed no significant effect, whereas PKC inhibition, particularly with BIM‐I, significantly reduced infection. To overcome BIM‐I's poor solubility and concentration‐dependent cytotoxicity, it is encapsulated into poly(lactic‐co‐glycolic acid) (PLGA)‐based nanoparticles. To enhance nanoparticle performance, stealth polymers like polyethylene glycol (PEG) are commonly incorporated. However, concerns about PEG immunogenicity have increased interest in alternatives like poly(2‐ethyl‐2‐oxazoline) (PEtOx). We formulated BIM‐I‐loaded nanoparticles containing either PEG or PEtOx and characterized them for their physicochemical properties, cytotoxicity, antiviral efficacy, and cellular uptake. Encapsulation improved the cellular tolerability of BIM‐I while preserving its antiviral activity. Confocal microscopy confirmed efficient uptake of all formulations, particularly PEGylated and PEtOxylated nanoparticles. These findings highlight nanoparticle‐mediated delivery of BIM‐I as a promising host‐directed antiviral strategy against IAV and support PEtOx as a viable PEG alternative in nanomedicine.

This study explores nanoparticle delivery of the protein kinase C inhibitor bisindolylmaleimide‐I (BIM‐I) to combat influenza A virus infections. Encapsulation in biodegradable PLGA nanoparticles improved safety while maintaining the compound's strong antiviral activity. Surface modification with PEG or PEtOx enhanced cellular uptake of the nanoparticles, highlighting a promising host‐directed nanomedicine approach and supporting PEtOx as a viable alternative to PEG.