Particle size and shape of cells are essential determining the outcome of drug delivery of nano carrier for medical applications. In this study, different size silver nanoparticles were controllably synthesized to treat two shapes of cells. Silver nanoparticles (AgNPs) were synthesized via chemical reduction using NaBH₄ and modified with polyvinylpyrrolidone (PVP) and bovine serum albumin (BSA) or encapsulated in liposomes to enhance cellular uptake. Different nanoparticle sizes were obtained as follows: uncapped AgNPs (30 nm), PVP–AgNPs (34.7 nm), BSA–AgNPs (113.9–145.2 nm), and liposome-encapsulated AgNPs (70.9–142.0 nm). Liposomes with a 5:3 molar ratio of dipalmitoylphosphatidylcholine (DPPC) -to-cholesterol formed stable vesicles, each encapsulating up to 66 AgNPs at a concentration of 2 mmol/L. Cytotoxicity assays revealed that uncapped 2 mM AgNPs exhibited strong toxicity toward both Caco-2 and U251 cells (IC₅₀: 13.52 µmol/L at 24 h). Liposomal AgNPs displayed concentration-dependent effects, with 1 mM AgNPs–liposomes exhibiting the highest toxicity toward Caco-2 cells (IC₅₀: 0.5 µmol/L at 24 h), but significantly lower toxicity toward U251 cells (IC₅₀: 134.3 µmol/L at 24 h). The formulation exhibiting the highest toxicity at 48 h was 2 mmol/L AgNPs–liposomes against Caco-2 cells (IC₅₀: 4.6 µmol/L). In contrast, BSA and PVP coatings significantly reduced toxicity, with IC₅₀ of 2.2 µmol/L for 50 mmol/L BSA–AgNPs and 14.9 µmol/L for 50 mmol/L PVP–AgNPs in Caco-2 cells. Liposome-encapsulated AgNPs showed enhanced toxicity against square-shaped Caco-2 cells compared to fibroblast-like U251 cells (p < 0.05), highlighting their potential for targeted cancer therapy. The findings of this study demonstrate that surface modifications and encapsulation strategies critically influence the biological effects of AgNPs in liposomes, providing a promising approach for enhanced anticancer activity.