Recent breakthroughs in mRNA therapeutics have transformed vaccine development, largely powered by lipid nanoparticle (LNP) based delivery systems. However, these systems exhibit a strong hepatic tropism, making them suboptimal for targeting extrahepatic organs such as the brain, lungs, pancreas, heart, and tumor tissues critical to non-vaccine therapeutic applications. This review explores next-generation delivery strategies designed to overcome liver centric distribution. We highlight emerging platforms, including pKa-tuned LNPs, polymeric and peptide-based carriers, exosomes, and biomimetic vesicles, along with physical enhancement techniques such as ultrasound, laser, and MRI-guided systems. Nonetheless, researchers are achieving more precise delivery to deep seated tissues by integrating these technologies with targeted ligands and responsive release mechanisms. Applications in oncology, cardiology, pulmonology, and neurology are discussed with a focus on preclinical and early clinical outcomes. Regulatory considerations, including immunogenicity, biodistribution, and manufacturing scalability, are also reviewed. Ultimately, this article presents a forward-looking perspective on engineering safe, organ specific mRNA delivery platforms beyond the liver, enabling the advancement of precision therapeutics. This review will provide a timely and comprehensive overview of innovative strategies to overcome these challenges, focusing on non-vaccine applications.

Bacterial vaginosis (BV) is a highly prevalent vaginal infection characterized by a dysbiotic shift in the vaginal microbiota, with Gardnerella vaginalis acting as a principal pathogen. Despite its association with adverse reproductive outcomes, BV remains underexplored from both mechanistic and therapeutic standpoints. Standard antibiotic regimens frequently fail due to high recurrence rates driven by multidrug-resistant (MDR) G. vaginalis strains and biofilm formation. In response, natural compounds and nutraceuticals, owing to their intrinsic antibacterial, antibiofilm, and immunomodulatory properties, have emerged as promising candidates for alternative BV therapies. In this paper, we first compile and critically evaluate preclinical and clinical evidence on the efficacy of plant extracts, essential oils (EOs), probiotics, vitamins, proteins, fatty acids, and enzymes against G. vaginalis, emphasizing their mechanistic insights in restoring vaginal microbial balance. Next, we focus on the integration of these bioactive agents into engineered nanosystems, such as lipid-based nanoparticles (LNPs), polymeric carriers, and inorganic nanostructures, to overcome limitations related to solubility, stability, and targeted delivery. Nonetheless, comparative studies, combination therapies, and recent patent developments are discussed to highlight how naturally derived molecules can enhance antimicrobial potency and reduce cytotoxicity. In conclusion, these platforms demonstrate superior in vitro and in vivo efficacy, offering a paradigm shift in the management of BV. Key challenges include scalable manufacturing, regulatory approval, and comprehensive safety assessment. Future research should prioritize standardized nanoparticle (NP) synthesis, detailed pharmacokinetic and toxicity profiling, and well-designed clinical trials to validate nature-inspired, nanoengineered therapies against G. vaginalis-induced BV.