Small Interfering RNA Approaches for Targeting Nicotinic Acetylcholine Receptors: Current Evidence and Therapeutic Perspectives.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that regulate diverse physiological processes in neuronal and non-neuronal tissues. In recent years, increasing evidence has shown that nAChRs are also expressed in many cancer cell types, where they contribute to tumor growth, survival, angiogenesis, migration, invasion, and resistance to therapy. The involvement of distinct receptor subunits in these processes has generated interest in nAChRs as potential therapeutic targets in oncology. However, conventional pharmacological agents often show limited subtype selectivity and may produce off-target effects because of the widespread distribution of these receptors in normal tissues. Small interfering RNA (siRNA) offers a more selective strategy by enabling sequence-specific silencing of individual nAChR subunits implicated in malignant behavior. This review highlights the structural and functional characteristics of nAChRs, the rationale for targeting specific subunits in cancer, and the mechanisms by which siRNA can suppress receptor expression. Particular attention is given to experimental studies evaluating the silencing of nAChR subunits in cancer models and to the therapeutic implications of combining receptor-specific siRNA with established anticancer agents. In addition, key translational barriers are discussed, including delivery challenges, instability, off-target effects, immune activation, and tumor heterogeneity. Although the field remains largely preclinical, available findings support the concept that nicotinic receptor-specific siRNA may serve as a promising precision strategy for cancer treatment and may improve treatment responsiveness in selected malignancies.