Nitric oxide tuning enhances cytotoxicity and reduces inflammation in prostate cancer nanotherapy.

Modulating intracellular nitric oxide (NO) levels offers a promising strategy to enhance tumor cell sensitivity to nanoparticle-based therapies. In this study, we investigated the impact of intracellular NO modulation in prostate cancer cells (PC3) using S-nitrosoglutathione (GSNO, a NO donor) and L-nitro arginine methyl ester (l-NAME, a nitric oxide synthase (NOS) inhibitor), in combination with cisplatin-loaded zinc oxide nanoparticles (ZnO/CisPt NPs). These nanoparticles, previously shown to exert selective cytotoxicity against PC3 cells, had their therapeutic performance further enhanced by NO modulation, which led to reduced NOS expression and regulation of inflammatory cytokines. Interestingly, both the increase and the depletion of intracellular S-NO levels contributed to tumor cell sensitization to the nanoparticle-based treatment. These results indicate that altering NO balance, regardless of direction, plays a key role in how cells respond to therapy. Our results reinforce the relevance of NO signaling in augmenting the efficacy of nanomedicine approaches while minimizing tumor-associated inflammation, offering a safer and more targeted strategy for prostate cancer treatment with potential for broader applications in oncology.