Messenger RNA (mRNA) has received great attention in the prevention and treatment of various diseases due to the success of COVID-19 mRNA vaccines (Comirnaty and Spikevax). To meet the therapeutic purpose, it is required that mRNA must enter the target cells and express sufficient proteins. Therefore, the development of effective delivery systems is necessary and crucial. Lipid nanoparticle (LNP) represents a remarkable vehicle that has indeed accelerated mRNA applications in humans, as several mRNA-based therapies have already been approved or are in clinical trials. In this review, we focus on mRNA-LNP mediated anticancer therapy. We summarize the main development strategies of mRNA-LNP formulations, discuss representative therapeutic approaches in cancer, and point out current challenges and possible future directions of this research field. We hope these delivered messages could help further improve the application of mRNA-LNP technology in cancer therapy. This article is protected by copyright. All rights reserved.

Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy.

mRNA vaccines have emerged as a revolutionary tool to generate rapid and precise immune responses against infectious diseases and cancers. Compared with conventional vaccines such as inactivated viruses, viral vectors, protein subunits or DNA-based vaccines, mRNA vaccines stand out owing to multiple advantages, including simplicity of design, fast production, enhanced safety and high efficacy. Nevertheless, efficient and targeted delivery of mRNA molecules remains a significant challenge owing to their inherent instability and susceptibility to degradation. Nanotechnology offers innovative solutions to surmount these obstacles and amplify the potency of mRNA vaccines. This Primer aims to outline a modular approach to developing biomaterials and nanotechnology for mRNA vaccines, with a focus on particle design, formulation evaluation and therapeutic applications. We delve into the underlying mechanisms of nanoparticle-facilitated mRNA protection, cellular uptake, endosomal escape and immune stimulation. We underscore the critical parameters that impact the manufacturing and clinical implementation of nanomaterial-based mRNA vaccines. Finally, we present the current limitations and future perspectives in the advancement of nanotechnology-enhanced mRNA vaccines for broad applications in prophylactic and therapeutic interventions. mRNA vaccines produce rapid and precise immune responses against infectious diseases and cancers. Chen et al. discuss the development of biomaterials and nanotechnology for mRNA vaccines, how these are designed and evaluated and the underlying mechanisms of cellular uptake and immune stimulation. 

Nanotechnology-based mRNA vaccines

Exosomes, which are nanosized vesicles secreted by cells, are attracting increasing interest in the field of biomedical research due to their unique properties, including biocompatibility, cargo loading capacity, and deep tissue penetration. They serve as natural signaling agents in intercellular communication, and their inherent ability to carry proteins, lipids, and nucleic acids endows them with remarkable therapeutic potential. Thus, exosomes can be exploited for diverse therapeutic applications, including chemotherapy, gene therapy, and photothermal therapy. Moreover, their capacity for homotypic targeting and self-recognition provides opportunities for personalized medicine. Despite their advantages as novel therapeutic agents, there are several challenges in optimizing cargo loading efficiency and structural stability and in defining exosome origins. Future research should include the development of large-scale, quality-controllable production methods, the refinement of drug loading strategies, and extensive in vivo studies and clinical trials. Despite the unresolved difficulties, the use of exosomes as efficient, stable, and safe therapeutic delivery systems is an interesting area in biomedical research. Therefore, this review describes exosomes and summarizes cutting-edge studies published in high-impact journals that have introduced novel or enhanced therapeutic effects using exosomes as a drug delivery system in the past 2 years. We provide an informative overview of the current state of exosome research, highlighting the unique properties and therapeutic applications of exosomes. We also emphasize challenges and future directions, underscoring the importance of addressing key issues in the field. With this review, we encourage researchers to further develop exosome-based drugs for clinical application, as such drugs may be among the most promising next-generation therapeutics. 

Recent advances in extracellular vesicles for therapeutic cargo delivery.

mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating the immune system. With regard to mRNA vaccines, researchers have modified the mRNA structure to enhance its stability and promote systemic tolerance of antigenic presentation in non-inflammatory contexts. Still, delivery of naked modified mRNAs is inefficient and results in low levels of antigen protein production. As such, lipid nanoparticles have been utilized to improve delivery and protect the mRNA cargo from extracellular degradation. This advance was a major milestone in the development of mRNA vaccines and dispelled skepticism about the potential of this technology to yield clinically approved medicines. Following the resounding success of mRNA vaccines for COVID-19, many other mRNA-based drugs have been proposed for the treatment of a variety of diseases. This review begins with a discussion of mRNA modifications and delivery vehicles, as well as the factors that influence administration routes. Then, we summarize the potential applications of mRNA-based drugs and discuss further key points pertaining to preclinical and clinical development of mRNA drugs targeting a wide range of diseases. Finally, we discuss the latest market trends and future applications of mRNA-based drugs. 

mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications

The limitations of conventional cancer treatment are driving the emergence and development of nanomedicines. Research in liposomal nanomedicine for cancer therapy is rapidly increasing, opening up new horizons for cancer treatment. Liposomal nanomedicine, which focuses on targeted drug delivery to improve the therapeutic effect of cancer while reducing damage to normal tissues and cells, has great potential in the field of cancer therapy. This review aims to clarify the advantages of liposomal delivery systems in cancer therapy. We describe the recent understanding of spatiotemporal fate of liposomes in the organism after different routes of drug administration. Meanwhile, various types of liposome-based drug delivery systems that exert their respective advantages in cancer therapy while reducing side effects were discussed. Moreover, the combination of liposomal agents with other therapies (e.g. photodynamic therapy; photothermal therapy, etc.) which allows for higher tumor-targeting efficiency and therapeutic efficacy was systematically evaluated. Finally, the opportunities and challenges faced by the field of liposome nanoformulations for entering the clinical treatment of cancer are highlighted. 

Recent advances and clinical translation of liposomal delivery systems in cancer therapy.

The success of messenger RNA therapeutics largely depends on the availability of delivery systems that enable the safe, effective and stable translation of genetic material into functional proteins. Here we show that extracellular vesicles (EVs) produced via cellular nanoporation from human dermal fibroblasts, and encapsulating mRNA encoding for extracellular-matrix α1 type-I collagen (COL1A1) induced the formation of collagen-protein grafts and reduced wrinkle formation in the collagen-depleted dermal tissue of mice with photoaged skin. We also show that the intradermal delivery of the mRNA-loaded EVs via a microneedle array led to the prolonged and more uniform synthesis and replacement of collagen in the dermis of the animals. The intradermal delivery of EV-based COL1A1 mRNA may make for an effective protein-replacement therapy for the treatment of photoaged skin. 

/pdf/intradermally-delivered-mrna-encapsulating-extracellular-2062jqux.pdf

Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy.

Abstract Or128: Exosomes carrying VEGF-A mRNA rescues ischemic tissue with low immunogenicity

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Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy.

Abstract Or128: Exosomes carrying VEGF-A mRNA rescues ischemic tissue with low immunogenicity