Pulmonary diseases are emerging as one of the leading causes of mortality worldwide, intensifying the urgent need for effective therapeutic interventions. mRNA therapeutics have attracted significant attention due to their therapeutic potential and may represent a new treatment strategy for pulmonary diseases. Delivering mRNA to the lungs via inhalation offers advantages, such as increased local drug concentration and reduced systemic exposure, presenting significant potential to meet the clinical needs of pulmonary diseases. However, the delivery process faces great challenges due to the physicochemical properties of mRNA and the lung's defense mechanisms. This review summarizes recent advancements in mRNA therapeutics for pulmonary inhalation delivery, highlighting the challenges faced in mRNA drug delivery to the lungs. Furthermore, the carrier design for inhaled mRNA delivery and its applications in pulmonary diseases were comprehensively discussed. Finally, we clarify the challenges that inhaled mRNA therapy must overcome before widespread clinical use, aiming to provide more efficient and safe therapeutic options for future pulmonary disease treatments.

Restoring P53's autonomous anti-cancer function through P53 mRNA delivery is a promising anti-tumor strategy. Yet, in tumors harboring mutant P53, the existing mutant P53 (Mutp53) would interferes with the anti-tumor function of Wtp53 through dominant-negative effect. Herein, we designed Vir-Z@R, a P53-repair nanosystem based on a virus-mimicking nanostructure to deliver P53 mRNA and Zn(II) into tumor cells. By supplementing Wtp53 through P53 mRNA delivery and promoting the degradation of mutant P53 via a zinc ion-mediated proteasomal pathway, Vir-Z@R restores the autonomous tumor-suppressive function of P53 and induce tumor cell death through multiple mechanisms (interfering with energy metabolism and inducing apoptosis), leading to delayed tumor growth and prolonged survival in mice with Mutp53. This study provides a strategy for treatment of P53-mutant tumor.

Antisense oligonucleotide (ASO) for anti-apoptosis is emerging as a highly promising therapeutic agents for ischemic stroke with complex pathological environment. However, its therapeutic efficacy is seriously limited by a number of challenges including inefficient internalization, low blood-brain barrier (BBB) penetration, poor stability, and potential toxicity of the carrier. Herein, a carrier-free programmed spherical nucleic acid nanostructure is developed for effective ischemic stroke therapy via integrating multifunctional modules into one DNA structure. By co-encoding caspase-3-ASO and transferrin receptor (TfR) aptamer into circle template, the spherical nucleic acid nanostructure (TD) was obtained via self-assembly. The experimental results demonstrated that the developed TD displayed efficient BBB penetration capability (6.4 times) and satisfactory caspase-3 silence effect (2.3 times) due to the dense DNA packaging in TD. Taken together, our study demonstrated that the carrier-free programmed spherical nucleic acid nanostructure could significantly improve the therapeutic efficacy of ischemic stroke and was a promising therapeutic tool for various brain damage-related diseases.