Sodium chloride nanoparticles as urinary bladder cancer therapeutics

In 2025, bladder cancer ranks sixth in incidence and tenth in cancer mortality in the United States, with an estimated 84,870 new cases and 17,420 deaths. Surgical transurethral resection of bladder tumors (TURBT) is the first step in standard bladder cancer treatment, followed by adjuvant intravesical chemotherapy or immunotherapy to eliminate existing or residual tumors. Local-regional therapy is particularly effective for bladder cancer because it targets superficial cases and maximizes therapeutic exposure, resulting in improved anticancer effect. Ion homeostasis is critical for maintaining cellular integrity and ensuring proper cell function. The balance between ion influx and efflux is tightly regulated by ion channels and transporters. While several strategies have been developed to target ion homeostasis as potential anticancer agents, including channel blockers and ionophores, the sodium chloride nanoparticle strategy may offer additional advantages in the context of cancer therapy.Immunogenic cell death (ICD) is a unique form of regulated cell death that promotes an anti-tumor immune response and contributes to the success of several cancer therapies such as cisplatin and mitoxantrone (MTX). ICD is characterized by damage-associated molecular patterns (DAMPs), including calreticulin (CRT), ATP, and HMGB1, which engage pattern-recognition receptors on antigen presenting cells, promoting dendritic-cell maturation and cross-presentation to T cells. Nanoparticle platforms that trigger ICD have shown promise in augmenting conventional therapies. We recently found that sodium chloride nanoparticles (SCNPs) not only kill bladder cancer cells but also induce ICD, positioning them as competitive immunotherapeutics. In this study, we presented a novel approach using phospholipid-coated sodium chloride nanoparticles (PSCNPs) as a potential treatment for bladder cancer. We synthesized and characterized SCNPs of various sizes and coated them with a layer of DSPE-PEG(2000) Amine, resulting in PSCNPs that can be stably dispersed in aqueous solutions. We investigated the degradation, endocytosis, and effects of PSCNPs on cellular ion homeostasis, as well as their effects on cell viability and cell death mechanisms. Furthermore, we evaluated the ability of PSCNPs to induce ICD and their impact on the tumor microenvironment (TME) and major organs. Finally, we evaluated the therapeutic efficacy of PSCNPs in subcutaneous tumor models, both as a single treatment and in combination with alphaPD1. Our results suggest that PSCNPs hold promise as a novel and effective treatment for bladder cancer, with the potential to boost immunity and transform the tumor microenvironment without causing systemic toxicity.