Messenger RNA (mRNA) therapeutics are rapidly becoming a paradigm-shifting technology in the fields of vaccines and gene therapy. Nevertheless, the scalability and translatability of mRNA vaccines and therapeutics are currently hampered by the inherent physicochemical instability of mRNA-lipid nanoparticles (mRNA-LNPs) and the requirement for ultra-cold chain storage. Freeze-induced stress, dehydration-induced lipid reorganization, and the loss of nanoparticle structure and integrity during lyophilization are the major contributing factors to the compromised mRNA encapsulation efficiency, bioactivity, and redispersion properties. While molecular cryoprotectants such as sugars and polymers can suppress molecular degradation, such conventional cryoprotectants are frequently ineffective at preserving the supramolecular structure and integrity of mRNA-LNPs against the stresses of freezing, freeze-drying, and long-term storage. This article reviews nanomaterial-assisted stabilization of mRNA-LNP formulations across molecular, nanoscale, and solid-state mechanisms. It examines the current use of biopolymeric matrices, inorganic nanoplatforms, and hybrid nanomaterials to control ice crystallization, resist dehydration stresses, and preserve lipid integrity. The review also covers smart adaptive nanomaterials designed for controlled release, pulmonary delivery, and cold chain-independent reconstitution.
Khalil et al. (2026) studied this question.