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 proteincoupled 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 was 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.