Cancer is the leading cause of death worldwide, with an increasing trend in incidence. Early diagnosis and treatment are crucial for 50–70% of cancer cases. Tumor hypoxia, characterized by insufficient oxygenation of tissue, alters the course of cancer and its response to therapy. Hypoxia-inducible factors (HIFs) are the main therapy hurdles for cancer, affecting tumor cells’ proteomic and genomic changes. HIF-1α, HIF-2α, and HIF-3α are the major regulators of oxygen homeostasis, controlling the acute adaptation to hypoxia. HIF-1α is widely expressed in various cells and controls the acute adaptation to hypoxia. During hypoxia, HIF-1α accumulates, facilitating the interaction between HIF-1a and the transcriptional co-factor CREB-binding protein/E1A-binding protein p300. Problems with specificity, delivery, and safety have impeded the clinical application of RNA-based therapies. These include undesirable off-target effects, ineffective intracellular delivery, and the absence of delivery vehicles appropriate for the target organ and cell type. Adverse immune effects and tolerance issues are caused by pathogen-associated molecular pattern (PAMP) receptors. LncRNA study faces challenges due to the lack of conservation for many lncRNA species, which hinders translation of lncRNAs found in human cancer to pre-clinical mice research for therapeutic targeting. To achieve the desired effect, ideal RNA therapeutics should undergo comprehensive testing for immunogenicity, undergo chemical modification to enhance pharmacokinetics and pharmacodynamics, be administered with consideration for biodistribution sequences and intracellular escape methods, interact with the intended target specifically and potently, and be dosed at the right level.