Writing in Nature Biotechnology, Jinbi Tian, Khanh T. M. Tran, and colleagues describe AGENT, short for Algorithm-Guided Experimental design for lipid Nanoparticle Thermostabilization. The platform couples high-throughput experimentation with Bayesian optimization, a machine-learning strategy that is specifically built for situations where every experiment is costly and data are scarce. Rather than screening thousands of candidate formulations blindly, AGENT extracts the maximum amount of information from each small batch of results, using Gaussian process models to predict how untested excipient combinations will behave and to decide which experiments to run next.

The formulation problem the team tackled is genuinely multidimensional. To convert liquid mRNA–lipid nanoparticles into a solid-state, water-free product, the researchers used vacuum drying and then had to identify a cocktail of excipients—sugars, buffers, and other stabilizing agents—that would preserve the nanoparticles’ structure and the mRNA’s bioactivity through drying and subsequent storage. The search space of possible excipient types, ratios, and concentrations is enormous, and the relationships between composition and stability are nonlinear and poorly understood. Traditional one-factor-at-a-time approaches, the authors note, have been constrained by narrow formulation scope and low-throughput screening, which is precisely why prior stabilization efforts have progressed slowly.

Bayesian optimization changes the economics of that search. The algorithm maintains a probabilistic model of the entire design space and, at each iteration, balances exploration of uncertain regions against exploitation of promising ones, typically using an expected-improvement acquisition function to select the next experiment. Implemented within the AutODEx platform developed at MIT’s Computer Science and Artificial Intelligence Laboratory, AGENT completed its optimization in just six iterative rounds within a single month—a pace that would be unattainable with conventional design-of-experiments workflows, which often require many more cycles and far more material to converge on an optimum.

The results are striking. The team worked with two clinically relevant lipid nanoparticle systems, one based on SM-102, the ionizable lipid in Moderna’s vaccine, and the other on ALC-0315, used by Pfizer-BioNTech. After optimization, both were converted into solid-state formulations that retained 100 percent of their bioactivity after more than two months of storage at 37 degrees Celsius—roughly human body temperature. For a class of products that normally degrades within hours or days at room temperature, that level of thermal tolerance represents a qualitative leap, and it was achieved without altering the core lipid compositions already validated in clinics.

Stability on the shelf means little if the vaccine no longer works in the body, so the researchers subjected their thermostable formulations to a demanding battery of animal tests. In rodents, solid-state SARS-CoV-2 vaccine formulations delivered by standard injection induced antigen-specific immune responses that were non-inferior to those elicited by freshly prepared liquid vaccines given intramuscularly. The team then pushed the concept further, incorporating the stabilized nanoparticles into microneedle patches—tiny arrays of dissolving needles that painlessly deliver vaccine into the skin and could, in principle, be mailed to patients or administered by minimally trained personnel.

The microneedle experiments extended into non-human primates, a critical translational step. Patch delivery of the thermostable solid-state vaccine in cynomolgus monkeys again produced antigen-specific immune responses comparable to conventional intramuscular injection of freshly prepared vaccine. Because microneedle patches eliminate the need for needles, syringes, and highly trained injectors, and because the solid-state formulation removes the need for refrigeration, the combination addresses two of the most persistent bottlenecks in global immunization campaigns simultaneously.

The significance of the work extends beyond any single vaccine. The mRNA–LNP platform is now being pursued for cancer immunotherapies, gene editing, and treatments for rare genetic diseases, and all of these applications inherit the same storage fragility. Solid-state, water-free formulations open the door to integrating mRNA payloads into emerging delivery modalities, from microneedle patches to other advanced systems, that would be incompatible with a liquid product requiring ultra-cold handling. The authors also point out that the cold chain carries substantial economic and environmental costs, with estimates suggesting that vaccine distribution inefficiencies contribute significantly to global inequity in immunization coverage.

Methodologically, the study adds to a growing body of evidence that Bayesian optimization can compress discovery timelines in materials science and pharmaceutical development, where experiments are expensive and the parameter space is combinatorially large. Similar approaches have accelerated the identification of 3D printing materials and complex heterostructures, and the MIT team has made both its datasets, deposited in a public Zenodo repository, and its source code openly available, lowering the barrier for other laboratories to adopt the workflow. The optimization framework treats excipient selection as a multi-objective problem, allowing researchers to specify what matters—potency retention, storage stability, manufacturability—and let the algorithm navigate trade-offs automatically.

Caveats remain before thermostable mRNA vaccines reach clinics. The reported storage data cover months rather than years, and regulatory agencies will require extensive documentation of long-term stability, manufacturing consistency, and safety under Good Manufacturing Practice conditions. Human clinical trials of solid-state formulations and microneedle delivery lie ahead. Yet the demonstration that AI-guided experimentation can find stabilizing excipient compositions in six iterations and one month suggests that the development bottleneck may no longer be the search itself. If the approach generalizes across payloads and lipid systems, the freezer—and the costly, fragile supply chain it demands—could finally become optional for mRNA medicine.

Subject of Research: AI-guided optimization of thermostable solid-state mRNA–lipid nanoparticle vaccine formulations

Article Title: Accelerated discovery of thermostable mRNA–lipid nanoparticle vaccines using data-efficient AI

Article References: Tian, J., Tran, K. T. M., Pogostin, B. H., Sheridan, O., Mursalova, S., Lee, A. H., Liu, S., Hamkins, J., Antov, D., Power, A. L., Dash, Z. S., Yun, D., Konaković Luković, M., Langer, R. S., & Jaklenec, A. (2026). Accelerated discovery of thermostable mRNA–lipid nanoparticle vaccines using data-efficient AI. Nature Biotechnology. https://doi.org/10.1038/s41587-026-03331-w

Image Credits: AI Generated

DOI: 10.1038/s41587-026-03331-w

Keywords: mRNA vaccines, lipid nanoparticles, Bayesian optimization, thermostability, cold chain, microneedle patches, vacuum drying, excipients, SARS-CoV-2, drug delivery, machine learning, Nature Biotechnology

The problem begins with a paradox inherent to phages themselves. These viruses are essentially nucleic acids wrapped in protein coats, decorated with tail fibers and baseplate structures that must remain precisely folded to recognize and inject their genetic payload into bacterial hosts. Unlike small-molecule drugs, which can often tolerate considerable environmental variation, phage infectivity depends on conformational integrity at the nanometer scale. A tail fiber that unfolds, a capsid that cracks, or a protein subunit that detaches can render a particle noninfectious even though the genetic material remains fully intact. Liquid formulations, which are preferable for many clinical settings because they avoid the stresses and costs of lyophilization, expose particles continuously to the surfaces of their containers, to each other, and to solution conditions that shift subtly over time.

Surface adsorption is the first and often the fastest loss mechanism. Phage particles, like many proteins, carry a mosaic of charged and hydrophobic patches that attract them to interfaces. Glass vials, plastic syringes, rubber stoppers and tubing all present surfaces to which virions can adhere, sometimes irreversibly. For low-concentration preparations, intended for pediatric dosing or for phages that are difficult to propagate to high titers, even a small fraction of adsorbed particles can translate into a clinically significant loss of dose. The study underscores that adsorption is not uniform across container materials: hydrophobic polymers tend to sequester particles more aggressively than borosilicate glass, but glass introduces its own risks through leached metal ions and alkaline surface chemistry. The authors emphasize that adsorption must be evaluated for every combination of phage, container and buffer, because a formulation that works beautifully for one phage type may fail entirely for another.

The second threat, aggregation, arises when particles collide and stick together, forming dimers, larger clusters and eventually visible precipitates. Aggregation is driven by electrostatic attraction between oppositely charged regions of adjacent particles, by hydrophobic interactions between exposed protein patches, and by the removal of stabilizing hydration shells during freezing and thawing or during shifts in ionic strength. Aggregated phages are problematic on multiple levels. Aggregates sediment during storage, creating heterogeneous dosing; they are cleared more rapidly from the bloodstream after injection; and they can trigger immune responses or exceed particulate limits set by pharmacopoeial standards for injectable products. Crucially, aggregation and infectivity loss are not always correlated in simple ways, which means that turbidity measurements or particle counts alone cannot substitute for plaque assays when assessing formulation quality.

The third mechanism, structural degradation, is the slowest but perhaps most insidious. Over weeks and months in liquid storage, capsid proteins can undergo deamidation, oxidation and backbone cleavage, while tail structures can gradually lose the precise geometry required for host recognition. Temperature accelerates these processes dramatically, which is why cold-chain dependence has been such a burden on phage therapy programs. The research highlights that structural degradation is often detected only through functional assays: a formulation may look perfectly clear and show normal particle counts by electron microscopy, yet exhibit a steady decline in plaque-forming units as more and more particles lose their ability to infect. This decoupling of appearance from activity is a central argument for rigorous, infectivity-based stability testing.

Against this backdrop, the study evaluates the protective roles of specific classes of excipients, the pharmaceutically accepted, nonactive ingredients that surround the phage in the final product. Sugars and sugar alcohols, including sucrose, trehalose and mannitol, emerge as foundational stabilizers. These molecules act through preferential exclusion, a thermodynamic effect in which the sugar is excluded from the surface of the protein, effectively making the folded state energetically favorable and discouraging both unfolding and aggregation. Trehalose in particular has a long history in the stabilization of biological drugs and vaccines, and the findings reinforce its value for phages, where it buffers particles against osmotic shocks and reduces interfacial stress. Polysorbates and other nonionic surfactants occupy a complementary niche: by adsorbing competitively to container surfaces and air-liquid interfaces, they deny phage particles access to the very interfaces where adsorption and surface-induced denaturation occur. Even low concentrations of surfactant can dramatically reduce the fraction of virions lost to a plastic syringe barrel.

Amino acids and buffering agents form the third pillar of the protection strategy. Arginine, glycine and histidine appear repeatedly in biologics formulations because they disrupt electrostatic attractions that drive aggregation, while histidine buffer offers mild pH control near neutrality, where most phages are comfortable. Plasma proteins and serum albumin, historically used as catch-all stabilizers in early phage work, are discussed in the context of modern pharmaceutical expectations: although effective, animal-derived proteins raise regulatory and supply concerns, pushing formulators toward chemically defined alternatives. Salts deserve careful handling, the authors note, because ionic strength simultaneously affects electrostatic repulsion between particles, adsorption to charged surfaces and the osmotic environment of the capsid; there is no universally optimal salt concentration, and each phage-buffer-container system must be characterized empirically.

Perhaps the most practically important message of the work is that excipient effects are context-dependent and phage-specific. A tailed, contractile Myoviridae-like phage with a large, complex capsid responds differently to stress than a small, robust Podoviridae-like particle. The study therefore advocates a structured development workflow: characterize the phage’s isoelectric point and hydrodynamic behavior, screen a panel of excipient candidates across relevant pH ranges, stress-test the leading candidates with accelerated temperature challenges, and validate the winners under real storage conditions in the intended container closure system. Analytical tools discussed in the article include plaque assays for infectivity, dynamic light scattering and nanoparticle tracking for aggregation, electron microscopy for morphological integrity, and differential scanning fluorimetry or similar methods for probing thermal stability. Combining these orthogonal readouts, rather than relying on any single metric, gives formulators the confidence that a liquid product will remain potent throughout its shelf life.

The implications for the phage therapy field are considerable. Liquid formulations stored at standard refrigeration temperatures, or even at room temperature in optimized compositions, would remove one of the most burdensome logistics constraints on clinical deployment, particularly in regions where deep-freeze distribution is unreliable. Standardized, excipient-protected formulations would also simplify regulatory pathways, since regulators can evaluate excipient safety profiles that are already well established for other biologics. As phage products progress from bespoke compassionate-use preparations toward licensed medicines, the kind of systematic formulation science presented in this study will be indispensable. It transforms the stabilization of phages from a craft of trial and error into a rational engineering discipline, giving the next generation of antiviral antibacterials a fighting chance to arrive intact, potent and ready at the patient’s bedside.

Subject of Research: Use of pharmaceutical excipients to stabilize bacteriophages in liquid formulations by preventing surface adsorption, aggregation and structural degradation.

Article Title: Investigating the role of excipients in mitigating surface adsorption, aggregation and structural degradation in liquid phage formulations

Article References: Siafakas, E., Duong, H. T. T., & Iredell, J. R. (2026). Investigating the role of excipients in mitigating surface adsorption, aggregation and structural degradation in liquid phage formulations. npj Viruses. https://doi.org/10.1038/s44298-026-00233-1

Image Credits: AI Generated

DOI: 10.1038/s44298-026-00233-1

Keywords: bacteriophage, phage therapy, liquid formulation, excipients, trehalose, polysorbate, surface adsorption, aggregation, capsid stability, biologics formulation, antibiotic resistance, npj Viruses