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Pharmaceutics
Special Issues
Recent Advances in the Development, Characterization, and Stability Aspects of...
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Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: 20 December 2026 | Viewed by 18229

Editors

Dr. Ravi Maharjan

E-Mail Website
Guest Editor
Laboratory of Biopharmaceutics, Yonsei University, Songdo, Incheon 21983, Republic of Korea
Interests: mRNA vaccines; lyophilization; vaccine stability; continuous manufacturing
Special Issues, Collections and Topics in MDPI journals
Dr. Surin Hong

E-Mail Website
Guest Editor
Department of Biotechnology, College of Life Science, CHA University, Gyeonggi 13488, Republic of Korea
Interests: nanomaterial; drug delivery; nano biosensor; plasmonic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The rapid development and subsequent implementation of RNA-based vaccines during the global COVID-19 pandemic not only transformed the landscape of vaccine technology but also paved the way for novel therapeutic applications that were previously unimaginable. This particular Special Issue aims to compile and present the most recent and noteworthy advancements in the realm of RNA vaccine research, including but not limited to, lipid nanoparticle (LNP) formulation strategies, novel characterization methodology, cryoprotectants for lyophilization, and the impact of storage conditions on vaccine performance.

We extend a cordial invitation to researchers and scholars to submit their research or review article contributions to this Special Issue. Through state-of-the-art research and the promotion of collaborative efforts among scientists within this discipline, we hope to advance the collective understanding and practical applications of RNA technology. We strongly encourage authors to provide in-depth insights and comprehensive data that have the potential to inspire further research and development endeavors in this highly promising and rapidly evolving area of study.

Dr. Ravi Maharjan
Dr. Surin Hong
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • RNA-based vaccines
  • lyophilization
  • stability
  • gene therapy
  • formulation strategies
  • novel characterization
  • delivery systems
  • biopharmaceuticals
  • continuous manufacturing
  • AI/ML/digital twin

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Published Papers (5 papers)

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Review

45 pages, 2942 KB  
Review
Target-Product and Translational Design Principles for Inhalable RNA Nanomedicines
by Hossein Omidian, Sumana Dey Chowdhury and Luigi X. Cubeddu
Pharmaceutics 2026, 18(8), 918; https://doi.org/10.3390/pharmaceutics18080918 - 27 Jul 2026
Viewed by 407
Abstract
Inhalable ribonucleic acid (RNA) nanomedicines are emerging as versatile therapeutics for respiratory diseases and pulmonary metastases, enabling localized delivery of messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotides, microRNA (miRNA) mimics, self-amplifying RNA, and genome-editing systems. This review synthesizes the available evidence [...] Read more.
Inhalable ribonucleic acid (RNA) nanomedicines are emerging as versatile therapeutics for respiratory diseases and pulmonary metastases, enabling localized delivery of messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotides, microRNA (miRNA) mimics, self-amplifying RNA, and genome-editing systems. This review synthesizes the available evidence and argues that the field has moved beyond asking whether RNA can reach the lungs. The more consequential translational question is whether RNA cargo, nanocarrier, excipients, manufacturing process, inhalation device, and pulmonary target cell can be integrated into a reproducible therapeutic product. Current research demonstrates progress in disease-corrective mRNA expression, silencing of inflammatory and fibrotic pathways, mucosal vaccination, antiviral therapy, and localized cancer treatment, alongside advances in ionizable lipid nanoparticles, lipid–polymer hybrids, chitosan and polyethyleneimine (PEI) polyplexes, dendrimers, peptide carriers, biomimetic systems, and dry-powder formulations. Translational maturity, however, remains uneven. Many studies demonstrate carrier feasibility, reporter expression, or preclinical activity, whereas fewer establish device-compatible aerosolization, preservation of RNA integrity during processing, traversal of pulmonary barriers, target-cell engagement, repeat-dose tolerability, and clinically meaningful benefit. Development should therefore be target-defined, analytically gated, device-specific, and outcome-centered. Inhalable RNA nanomedicines are best understood as integrated pulmonary products whose success depends on preserving RNA function throughout manufacturing, aerosolization, post-deposition barrier navigation, intracellular delivery, and disease-relevant pharmacodynamic activity. Full article
(This article belongs to the Special Issue Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines)
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40 pages, 4675 KB  
Review
Next-Generation Nanocarrier Platforms for RNA Vaccines: Advances in Formulation, Stability Engineering, and Translational Manufacturing Challenges
by Mohannad M. Fallatah, Samiyah Al-Khaldi, Dimah K. Alrabiah, Ibrahim A. Alradwan, Mohammad N. Alkhrayef, Alhassan H. Aodah, Essam J. Alyamani, Esraa A. Aldkheil, Seham S. Alharthy, Najlaa A. Abualsaud, Yahya F. Jamous and Ahmad M. Aldossary
Pharmaceutics 2026, 18(8), 909; https://doi.org/10.3390/pharmaceutics18080909 - 23 Jul 2026
Viewed by 526
Abstract
RNA vaccines have emerged as an attractive platform for treating infectious diseases, cancer immunotherapy, and personalized medicine; however, their clinical success depends on multiple factors, including efficient, stable, and scalable delivery systems. Because RNA molecules are highly sensitive to factors such as enzymatic [...] Read more.
RNA vaccines have emerged as an attractive platform for treating infectious diseases, cancer immunotherapy, and personalized medicine; however, their clinical success depends on multiple factors, including efficient, stable, and scalable delivery systems. Because RNA molecules are highly sensitive to factors such as enzymatic degradation, oxidation, poor cellular uptake, and limited endosomal escape, nanocarrier platforms play essential roles in protecting RNA cargo and enabling effective intracellular delivery. The biological performance of RNA nanocarriers depends on efficient cellular uptake, endosomal escape, intracellular RNA delivery, biodistribution, and immune modulation. Comparative assessment emphasizes that lipid nanoparticles remain the most clinically mature approach, while nanostructured lipid carriers, polymeric systems, and exosome-based nanocarriers provide multiple benefits for stability, targeted delivery, biocompatibility, and/or controlled release. Translational challenges involving GMP manufacturing, batch reproducibility, regulatory expectations, and scale-up are considered critical for effective nano-based RNA vaccine delivery and are elaborated in this review. Emerging advances such as pKa-tuned ionizable lipids, ligand-targeted systems, stimuli-responsive nanocarriers, circular and self-amplifying RNA platforms, artificial intelligence-guided formulation design, and needle-free delivery technologies may further expand the safety, accessibility, and therapeutic potential of RNA vaccines. In this review, we highlight next-generation nanocarrier systems for RNA vaccines, with an emphasis on novel nanocarrier RNA vaccine delivery systems. Additionally, we evaluate stability engineering approaches that currently limit global vaccine distribution and the future of the nanocarrier platforms for RNA vaccines. Full article
(This article belongs to the Special Issue Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines)
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Figure 1

44 pages, 4955 KB  
Review
Analytical Characterization and Stability Assessment of RNA-Based Vaccines
by Hadi M. Alasmari, Shouq F. Alghannam, Hassan A. Al-Moammar, Dimah K. Alrabiah, Seham S. Al-Harthy, Essam J. Alyamani, Sami A. Alyahya, Mohammad Alkhrayef, Mohannad Fallatah, Samiyah Al-Khaldi, Abdulmalek T. Algarni, Yahya F. Jamous and Ahmad M. Aldossary
Pharmaceutics 2026, 18(7), 790; https://doi.org/10.3390/pharmaceutics18070790 - 27 Jun 2026
Viewed by 996
Abstract
Ribonucleic acid-based vaccines have emerged as one of the most significant advances in modern vaccine development, demonstrating remarkable clinical success and enabling rapid responses to emerging infectious diseases. Despite their therapeutic potential, the development of these vaccines remains challenging because of the inherent [...] Read more.
Ribonucleic acid-based vaccines have emerged as one of the most significant advances in modern vaccine development, demonstrating remarkable clinical success and enabling rapid responses to emerging infectious diseases. Despite their therapeutic potential, the development of these vaccines remains challenging because of the inherent instability of ribonucleic acid molecules, their susceptibility to degradation, and the complexity of formulation design. Ensuring product quality, stability, and biological performance therefore requires comprehensive analytical characterization throughout development, manufacturing, storage, and quality control. This review provides a comprehensive overview of current analytical strategies used to evaluate ribonucleic acid-based vaccine formulations. Key analytical approaches for assessing molecular integrity, purity, encapsulation efficiency, particle morphology, size distribution, surface characteristics, structural attributes, and biological potency are discussed. The review also examines the influence of formulation composition, lipid nanoparticle design, manufacturing processes, and storage conditions on vaccine stability and performance. In addition, major degradation pathways, critical quality attributes, and analytical challenges associated with quality assessment are highlighted. Furthermore, current regulatory considerations and limitations of existing analytical methodologies are discussed, particularly the challenges associated with establishing robust relationships between physicochemical properties and biological efficacy. The review emphasizes the importance of integrated multi-method analytical approaches for comprehensive characterization and quality assurance. Continued advances in analytical technologies and standardization efforts will be essential for supporting the development of safe, effective, and stable ribonucleic acid-based vaccines and for facilitating their broader pharmaceutical applications. Full article
(This article belongs to the Special Issue Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines)
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31 pages, 2007 KB  
Review
Artificial Intelligence-Driven Strategies for Targeted Delivery and Enhanced Stability of RNA-Based Lipid Nanoparticle Cancer Vaccines
by Ripesh Bhujel, Viktoria Enkmann, Hannes Burgstaller and Ravi Maharjan
Pharmaceutics 2025, 17(8), 992; https://doi.org/10.3390/pharmaceutics17080992 - 30 Jul 2025
Cited by 34 | Viewed by 7590
Abstract
The convergence of artificial intelligence (AI) and nanomedicine has transformed cancer vaccine development, particularly in optimizing RNA-loaded lipid nanoparticles (LNPs). Stability and targeted delivery are major obstacles to the clinical translation of promising RNA-LNP vaccines for cancer immunotherapy. This systematic review analyzes the [...] Read more.
The convergence of artificial intelligence (AI) and nanomedicine has transformed cancer vaccine development, particularly in optimizing RNA-loaded lipid nanoparticles (LNPs). Stability and targeted delivery are major obstacles to the clinical translation of promising RNA-LNP vaccines for cancer immunotherapy. This systematic review analyzes the AI’s impact on LNP engineering through machine learning-driven predictive models, generative adversarial networks (GANs) for novel lipid design, and neural network-enhanced biodistribution prediction. AI reduces the therapeutic development timeline through accelerated virtual screening of millions of lipid combinations, compared to conventional high-throughput screening. Furthermore, AI-optimized LNPs demonstrate improved tumor targeting. GAN-generated lipids show structural novelty while maintaining higher encapsulation efficiency; graph neural networks predict RNA-LNP binding affinity with high accuracy vs. experimental data; digital twins reduce lyophilization optimization from years to months; and federated learning models enable multi-institutional data sharing. We propose a framework to address key technical challenges: training data quality (min. 15,000 lipid structures), model interpretability (SHAP > 0.65), and regulatory compliance (21CFR Part 11). AI integration reduces manufacturing costs and makes personalized cancer vaccine affordable. Future directions need to prioritize quantum machine learning for stability prediction and edge computing for real-time formulation modifications. Full article
(This article belongs to the Special Issue Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines)
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22 pages, 2633 KB  
Review
Implications of Anaphylaxis Following mRNA-LNP Vaccines: It Is Urgent to Eliminate PEG and Find Alternatives
by Jinxing Song, Dihan Su, Hongbing Wu and Jeremy Guo
Pharmaceutics 2025, 17(6), 798; https://doi.org/10.3390/pharmaceutics17060798 - 19 Jun 2025
Cited by 12 | Viewed by 7522
Abstract
The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination [...] Read more.
The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination with mRNA-LNP vaccines. Meanwhile, the US Food and Drug Administration (FDA) has added four black-box warnings in the instructions for mRNA-LNP vaccines. Numerous studies have proven that the observance of side effects after vaccination is indeed positively correlated to the level of anti-PEG antibodies (IgM or IgG), which are enhanced by PEGylated preparations like LNP vaccine and environmental exposure. After literature research and review in the past two decades, it was found that the many clinical trial failures (BIND-014, RB006 fell in phase II) of PEG modified delivery system or PEGylated drug were related to the high expression of anti-PEG IgM and IgG. In the background of shooting multiple mRNA-LNP vaccines in billions of people around the world in the past three years, the level of anti-PEG antibodies in the population may have significantly increased, which brings potential risks for PEG-modified drug development and clinical safety. This review summarizes the experience of using mRNA-LNP vaccines from the mechanism of the anti-PEG antibodies generation, detection methods, clinical failure cases of PEG-containing products, harm analysis of abuse of PEGylation, and alternatives. In light of the increasing prevalence of anti-PEG antibodies in the population and the need to avoid secondary injuries, this review article holds greater significance by offering insights for drug developers. It suggests avoiding the use of PEG excipients when designing PEGylated drugs or PEG-modified nano-formulations and provides references for strategies such as utilizing PEG-free or alternative excipients. Full article
(This article belongs to the Special Issue Recent Advances in the Development, Characterization, and Stability Aspects of RNA-Based Vaccines)
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