The review lays out five interconnected processes that govern the fate of mRNA-lipid nanoparticles in the body: route-dependent transport and initial tissue distribution, interactions with blood proteins that form the so-called protein corona, receptor-mediated cellular uptake and organ tropism, endosomal escape and intracellular trafficking, and finally metabolic degradation and immune-mediated clearance. These pathways act sequentially, meaning that a change at any stage ripples through the entire pharmacokinetic profile. Crucially, the authors emphasize that the localization of LNP-associated lipids, intact mRNA, and encoded protein follows distinct spatial and temporal patterns, so detecting one component cannot be assumed to demonstrate the presence or activity of another. Apparent contradictions between studies using radiolabeling, molecular quantification, imaging, or protein-based readouts often reflect differences in the biological endpoint measured rather than genuinely conflicting results.

Administration route emerges as one of the most powerful determinants of biodistribution. Intramuscular and subcutaneous injection favor retention at the injection site followed by drainage to regional lymph nodes, with peak tissue concentrations typically occurring within two to eight hours; subcutaneous delivery produces similar patterns but with slower kinetics and prolonged persistence. Intravenous administration bypasses local lymphatics entirely, producing immediate systemic exposure with predominant accumulation in the liver. Respiratory delivery via intranasal, intratracheal, or nebulized routes deposits nanoparticles throughout the airway epithelium according to aerodynamic diameter, bypassing first-pass hepatic clearance and enabling mucosal immunity characterized by secretory IgA and tissue-resident memory T cells. The review notes, however, that intranasal delivery is not straightforward, as animal studies suggest some formulations may be reactogenic.

Perhaps the most striking examples of route-driven tropism come from less conventional approaches. Intraperitoneal administration of ionizable LNPs has been shown to deliver mRNA to pancreatic beta cells through an indirect mechanism in which peritoneal macrophages internalize the particles before transferring functional mRNA to pancreatic islets, largely avoiding the hepatic dominance seen after intravenous injection. More recently, researchers identified a pancreas-selective delivery mechanism based on organ capsule filtration, in which arginine-histidine-modified LNPs undergo protein-induced size enlargement after systemic administration, allowing preferential accumulation within the pancreatic capsule. This platform achieved efficient delivery of Cas9 mRNA and therapeutic cytokine mRNAs in rodents and non-human primates, demonstrating that particle size, protein association, organ anatomy, and administration route act synergistically to determine organ selectivity rather than lipid chemistry alone.

Intrathecal injection, which introduces nanoparticles directly into cerebrospinal fluid, bypasses the blood-brain barrier and enables widespread distribution across the brain and spinal cord. Biodegradable brain-targeting LNPs have achieved reporter expression in the cortex, hippocampus, and cerebellum, transfecting both neurons and astrocytes, while related work delivered CRISPR genome-editing components throughout the central nervous system with limited peripheral exposure. Notably, formulation chemistry remained a critical determinant even within this route, with ionizable lipid structure influencing both cellular uptake and regional distribution. Subretinal injection likewise places formulations directly adjacent to the retinal pigment epithelium and photoreceptors, enabling robust local transfection for inherited retinal disorders while minimizing systemic exposure. Even the choice of limb for sequential vaccine doses matters: murine studies showed enhanced early germinal center B-cell responses and higher-affinity antibodies following ipsilateral boosting, although these differences diminished over time, with comparable long-term protection regardless of injection side.

Once nanoparticles reach biological fluids, they rapidly adsorb plasma proteins to form a protein corona that replaces the synthetic surface as the interface recognized by cells. Apolipoprotein E is the best-characterized component, promoting uptake through low-density lipoprotein receptor family members and explaining the intrinsic hepatic tropism of many formulations. But quantitative proteomics reveals a far more complex picture: the corona is a dynamic mixture of high-density lipoproteins, albumin, vitronectin, complement proteins, immunoglobulins, fibrinogen, prothrombin, C-reactive protein, and alpha-2-macroglobulin, whose composition depends on lipid chemistry, administration route, and host physiology. HDL has been associated with enhanced uptake and transfection, albumin prolongs circulation by improving colloidal stability, and complement proteins and immunoglobulins accelerate clearance by the mononuclear phagocyte system, potentially contributing to complement activation-related pseudoallergy and anti-PEG immune responses during repeated dosing. Formulations with nearly identical physical properties can therefore exhibit markedly different tissue tropism because organ selectivity is determined by the integrated corona composition rather than any single protein.

Even successful cellular uptake does not guarantee productive delivery. The review identifies endosomal escape as the principal intracellular bottleneck, with only a small fraction of internalized nanoparticles releasing intact mRNA into the cytoplasm before lysosomal degradation. Ionizable lipids facilitate escape by becoming protonated within acidifying endosomes, destabilizing the endosomal membrane, but recent in vivo LysoTag and lysosomal barcoding studies have provided the first quantitative measurements of escape kinetics, showing that relatively small improvements in escape efficiency produce disproportionately large increases in protein expression. This finding shifts the focus of formulation optimization from maximizing tissue uptake toward improving intracellular trafficking and cytosolic release. Once released, mRNA undergoes ribosomal translation before rapid degradation by endogenous ribonucleases, while the encoded protein frequently persists considerably longer, creating a temporal dissociation between nanoparticle localization, mRNA persistence, and biological activity that explains why different analytical methods yield different pharmacokinetic profiles for the same formulation.

The human evidence, though less comprehensive, broadly supports the preclinical picture. After intramuscular vaccination, vaccine-derived mRNA and encoded spike protein can be transiently detected in plasma within the first few hours, consistent with systemic dispersion of a small fraction of the dose. Lymph node biopsies confirm local expression in germinal-center B cells and dendritic cells, correlating with strong antibody and T-cell responses. One study using RT-qPCR detected vaccine mRNA in lymph nodes, liver, spleen, and myocardium from recently vaccinated individuals, with persistence up to 30 days in some axillary lymph nodes, but the authors of that work concluded that observed cardiac changes likely reflected pre-existing conditions rather than direct vaccine effects. Quantitative imaging in non-human primates has found no evidence of significant mRNA or lipid presence in brain tissue, and examination of gonadal tissues reveals only trace, fragmented RNA species without functional translation. The placenta, meanwhile, appears to be selectively targetable: optimized ionizable LNPs efficiently transfected placental trophoblasts with minimal fetal transfer in pregnant mice and ex vivo human placental perfusion systems, opening possibilities for treating pre-eclampsia and fetal growth restriction.

Clearance kinetics are now better characterized as well. In most models, mRNA persists for less than 48 hours before enzymatic breakdown, while lipid components are metabolized more slowly through hepatic and biliary routes; PEG-lipids and cholesterol derivatives may remain for several days, particularly within macrophages, but are gradually cleared without significant histopathological changes. Mass spectrometry studies of a biodegradable ionizable lipid showed complete hepatobiliary and renal clearance by 168 hours despite rapid systemic distribution of lipid-derived radioactivity. Repeated exposure to PEG-containing formulations may induce anti-PEG antibodies and complement activation, leading to accelerated blood clearance and altered biodistribution after subsequent administrations, a phenomenon driving the development of PEG-free alternatives. Cross-species comparisons reveal that rodents tend to overestimate hepatic accumulation relative to humans, while non-human primates better replicate human plasma kinetics but differ in immune activation thresholds, prompting growing interest in organ-on-chip systems, organoids, and humanized models to improve translational accuracy.

Looking forward, the review argues that rational, data-driven engineering is replacing empirical formulation. Selective organ targeting (SORT) lipids redirect expression from liver to spleen, lung, or bone marrow in a charge-dependent manner; biodegradable ionizable lipids with ester or ketal linkages reduce long-term retention while maintaining delivery efficiency; and barcode-based screening now enables high-throughput evaluation of hundreds of formulations within a single animal. Artificial intelligence and machine learning are accelerating lipid design, with graph neural networks predicting blood-brain barrier permeability and generative models proposing novel ionizable structures, though the authors caution that most models are trained on small, heterogeneous datasets and require rigorous external validation. Physiologically based pharmacokinetic and quantitative systems pharmacology models are increasingly integrating these diverse data streams to predict tissue exposure and protein expression across species. The overarching message is clear: biodistribution cannot be defined by a single analytical signal, and progress toward clinically predictable mRNA therapeutics will depend on determining not only where each formulation distributes, but which cells receive intact cargo, whether functional expression occurs, and how long its effects persist.

Subject of Research: Biodistribution and pharmacokinetics of mRNA lipid nanoparticle delivery systems

Article Title: Mechanisms and determinants of mRNA Lipid Nanoparticle biodistribution: From pharmacokinetics to clinical translation

Article References: Alhareth, Z., & López‐Camacho, C. (2026). Mechanisms and determinants of mRNA Lipid Nanoparticle biodistribution: From pharmacokinetics to clinical translation. Bioengineering & Translational Medicine, Article e70183. https://doi.org/10.1002/btm2.70183

Image Credits: AI Generated

DOI: 10.1002/btm2.70183

Keywords: mRNA therapeutics, lipid nanoparticles, biodistribution, protein corona, endosomal escape, pharmacokinetics, drug delivery, SORT lipids, intrathecal delivery, placental transfer, PBPK modeling, clinical translation

The review, led by researchers at the University of Utah, examines why so many nanoparticle drug delivery systems stall before reaching patients. Only about twenty percent of nanoparticle-based delivery systems assessed in preclinical studies are ever considered for translational investigation, and the actual clinical translation rate is lower still, undermined by problems with stability, scalability, efficacy, and toxicity. Between 2001 and 2024, just 57 nanoparticle-based drugs advanced from Phase I and II trials into Phase III, and only 17 progressed through the first three phases into Phase IV. Most failures occur in Phase II, where lack of efficacy or unforeseen toxicity ends development. The authors contend that these repeated disappointments stem largely from the absence of integrative, predictive frameworks that systematically connect nanoparticle design, biological interactions, and clinical drug exposure.

The stakes of closing this gap were made vividly clear during the COVID-19 pandemic. Lipid nanoparticles carrying messenger RNA proved to be the linchpin of the Pfizer/BioNTech and Moderna vaccines, whose ionizable lipids protonate at acidic pH to complex and protect mRNA and then release it inside cells at endosomal pH. It has been estimated that the first year of COVID-19 vaccination alone prevented 14.4 million deaths. Yet biodistribution studies of these lipid nanoparticles revealed predominant accumulation in the liver, a finding that determines both efficacy and safety and underscores why quantitative pharmacokinetic analysis is essential for any nanoparticle system with organ-specific accumulation. Despite this landmark success, only two lipid nanoparticle products and no polymeric nanoparticles have been approved since Comirnaty, the first authorized mRNA vaccine.

The review catalogues the approved landscape to show both what has been achieved and how limited it remains. Of 75 nanomedicines approved by the FDA or the European Medicines Agency, 25 are lipid-based and 24 are polymer-based. As of February 2024, a search for nanoparticle therapeutics on ClinicalTrials.gov identified 164 clinical trials involving systemically administered nanoparticles, with most candidates languishing in early-phase testing. Lipid nanoparticles dominate systemic applications because they are weakly immunogenic, can encapsulate both hydrophilic and hydrophobic drugs, and are relatively easy to manufacture at scale. Polymeric nanoparticles follow, prized for biodegradability and controlled release but plagued by limited encapsulation of hydrophilic cargos and batch-to-batch variability. Protein-based nanoparticles, nanocrystals, and inorganic particles make up the remainder of the approved arsenal.

Central to the translation problem is a chronic shortage of high-quality pharmacokinetic data. Preclinical studies frequently measure only organ-level biodistribution at fixed time points, describing where nanoparticles travel without the mathematical rigor needed to characterize how fast they arrive, how long they persist, and how they are cleared. A meta-analysis compiling more than 2,000 nanoparticle datasets in mice found that 65 percent contained fewer than four time points—far too sparse for proper modeling. Moreover, most preclinical pharmacokinetic studies are conducted with the drug-loaded particle rather than the nanoparticle alone, making it impossible to decouple the contributions of carrier and cargo. Without tissue partition coefficients, organ-specific distribution data, and elimination parameters, even sophisticated models cannot predict clinical behavior accurately.

The physics and biology of nanoparticles make their behavior notoriously difficult to anticipate. Size, surface charge, shape, and composition all govern circulation time, uptake, and clearance, often in nonlinear ways. Particles of roughly 8 to 10 nanometers are typically removed by glomerular filtration in the kidney, yet mesoporous silica and polymeric particles as large as 200 nanometers have been detected in urine. PEG-coated particles up to 114 nanometers have crossed the blood-brain barrier despite intercellular spaces of only 20 to 60 nanometers. Particles larger than about one micrometer become trapped in capillaries and are swiftly engulfed by phagocytic cells. Surface chemistry adds another layer of complexity: PEGylation extends circulation by sterically shielding particles from opsonization, but anti-PEG antibodies can accelerate clearance, and pre-existing anti-PEG immunity has been shown to reduce tumor accumulation and circulating levels of lipid nanoparticles in mice.

Off-target effects compound these challenges. An estimated 95 percent of an administered nanoparticle dose is sequestered by the liver, spleen, and lungs and never reaches its intended target. Accumulation in filtration organs can trigger immune responses, and there is growing evidence that large doses can overwhelm the mononuclear phagocyte system, temporarily impairing its ability to respond to pathogens. Long-term biodistribution and clearance studies, essential for predicting chronic toxicity, remain sparse because they are expensive, time-consuming, and constrained by the short lifespans of laboratory animals. Pharmacokinetic modeling, the authors argue, can fill these voids by simulating multiple-dose regimens, predicting tissue accumulation, and extrapolating toxicity risk without requiring exhaustive animal studies.

To organize these efforts, the review introduces a framework called model-informed nanoparticle development, or MIND, which integrates prior knowledge of nanoparticle physicochemical properties, in vitro and in vivo biological data, and mechanistic modeling into a prospective decision-making pipeline. Within this framework, physiologically based pharmacokinetic (PBPK) models incorporate organ blood flows, tissue composition, and particle-specific processes such as size-dependent uptake, opsonization, and clearance by the mononuclear phagocyte system to predict human exposure from animal data—a critical capability for refining first-in-human dose selection. Population pharmacokinetic (PopPK) models, built on nonlinear mixed-effects approaches, capture variability across patients using sparse sampling, as demonstrated by a model of the nanoparticle-drug conjugate NLG207 developed from 27 patients in two Phase II trials, which revealed distinct kinetics between nanoparticle-bound and free camptothecin. Quantitative systems pharmacology models go further, embedding cellular pathways and disease mechanisms to explain how and why particles behave as they do. Bayesian methods and stochastic, Monte Carlo-based simulations add rigorous quantification of uncertainty and variability.

Real-world examples show what modeling can accomplish. A multiscale PBPK model of mesoporous silica nanoparticles in rats subdivided organs into vascular, extravascular, and phagocytic compartments and identified nanoparticle degradation rate, tumor blood viscosity, particle size, and vascular porosity as dominant determinants of tumor delivery. A gold nanoparticle model developed in mice was extrapolated to rats across 15 organ compartments with long-term simulations extending to 56 days, demonstrating the principle of interspecies scaling on which clinical translation depends. In neonates, where dosing errors are most dangerous, PBPK models built from adult intravenous data have been converted into neonatal models to generate dose recommendations where direct data are nearly impossible to collect. Machine learning is now being layered onto these approaches, optimizing manufacturing parameters and predicting quality attributes before production even begins.

Manufacturing remains a parallel hurdle, and one that modeling increasingly touches. Scale-up demands reproducible physicochemical properties with minimal batch variation, and intricate synthesis schemes often cannot survive industrial demands. The COVID-19 vaccines illustrated the alternative: a deliberately simple lipid nanoparticle design, built from well-characterized components, enabled global production of 19 million doses within months and more than 807 million doses distributed by Moderna alone in 2021. Quality-by-design procedures recommended by international harmonization guidelines, along with 12-month stability studies and roughly 95 percent purity targets, are raising the bar for nanoformulations, though long-term hydrolytic degradation of PEGylated and polymeric particles continues to erode shelf life.

The path forward, the authors conclude, requires culture change as much as technical advance. Regulators and industry have embraced model-informed drug development for small molecules and biologics, but have been slower to accept modeling strategies for nanomedicines, in part because standardized characterization and pharmacokinetic methods remain immature. The reviewers call for regulatory guidelines specifying simulation methods, validation criteria, and reporting standards for nanoparticle models, and for routine integration of real-time biodistribution data from PET imaging and omics datasets into model refinement. If the field adopts this model-informed mindset, the authors argue, the same quantitative rigor that carried mRNA vaccines to billions of arms can be brought to bear on the thousands of nanoparticle designs still waiting in the laboratory—accelerating the arrival of safer, more effective nanomedicines at the bedside.

Subject of Research: Use of pharmacokinetic modeling to overcome translational barriers in nanoparticle-based drug delivery

Article Title: From bench to bedside: Overcoming translational hurdles in nanoparticle research with pharmacokinetic modeling

Article References: Parrot, M., Xu, N., Adnan, M., Cave, J., Ghandehari, H., Nance, E., & Yellepeddi, V. (2026). From bench to bedside: Overcoming translational hurdles in nanoparticle research with pharmacokinetic modeling. Bioengineering & Translational Medicine, Article e70176. https://doi.org/10.1002/btm2.70176

Image Credits: AI Generated

DOI: 10.1002/btm2.70176

Keywords: nanoparticles, pharmacokinetic modeling, PBPK, PopPK, lipid nanoparticles, drug delivery, clinical translation, nanomedicine, biodistribution, MIND framework, toxicity, mRNA vaccines

The research team, led by Anja Schroff of the Department of Medical Radiation Sciences, set out to answer a deceptively simple question with major implications for both medicine and emergency preparedness. Iodine-131 is a workhorse of nuclear medicine, used for decades to treat hyperthyroidism and certain thyroid cancers, because the thyroid gland eagerly hoards iodine to build its hormones. But the same isotope is also a signature component of nuclear accident fallout. Understanding exactly how much radiation each organ receives after exposure — and whether that dose differs between males and females, or between the young and the grown — is essential both for optimizing therapy and for refining risk estimates after a nuclear emergency.

To probe the question, the researchers gave male and female Sprague–Dawley rats a controlled internal exposure of 0.36 megabecquerels of iodine-131 at one of two life stages: five weeks of age, representing a young, still-developing animal, and seventeen weeks of age, representing adulthood. Over the following six days, they measured the activity concentration of the isotope in sixteen vital tissues at six time points, ranging from one hour to 144 hours after injection. From these time-activity data, they calculated the mean absorbed dose delivered to each organ, using both analytical methods and Monte Carlo simulations to cross-check their estimates.

The results were striking. As expected, the thyroid gland dominated the picture, showing the highest iodine-131 activity concentration of any tissue in every group — peaking at 18 hours after exposure in males and 24 hours in females, regardless of whether the animals were young or adult. Every other tissue lagged far behind, with the stomach, which also expresses iodine-transporting machinery, coming in a distant second. But the real story lay in the differences between groups, which proved to be anything but subtle.

Female rats consistently accumulated more iodine-131 in their thyroids than males, and — critically — they retained it longer. That combination of higher uptake and slower clearance translated directly into higher radiation dose. The absorbed dose to the thyroid ranged across the study groups from 23 gray per megabecquerel in adult males to a staggering 100 gray per megabecquerel in young females — a more than fourfold difference driven entirely by biological sex and age at exposure. Statistically significant sex differences emerged in all sixteen tissues examined, with the most pronounced effect in the thyroid itself.

Age mattered too, though in a sex-specific way. The most notable age-related differences in thyroid uptake and absorbed dose appeared in males: young males showed markedly higher iodine-131 uptake than adult males, resulting in a substantially greater thyroid dose. In females, whose thyroid uptake was already elevated, the age effect was less prominent. This pattern suggests that the developing thyroid — or the hormonal and metabolic milieu surrounding it — handles iodine differently depending on both its maturity and the animal’s sex, compounding rather than simply adding to the sex effect.

To understand the mechanism behind these differences, the team turned to the sodium-iodide symporter, or NIS, the membrane protein responsible for actively pumping iodide into thyroid cells. Using immunohistochemistry and western blot analysis, they quantified NIS protein expression in thyroid tissue across all groups. The result was a surprise: despite the dramatic differences in uptake and dose, NIS protein levels showed high individual variability but no clear, consistent difference between the groups. Whatever drives females and young animals to accumulate and retain more radioactive iodine, it appears not to be a simple matter of having more of the iodine transporter — hinting at deeper biological factors, perhaps involving hormone regulation, thyroid size, iodine turnover kinetics, or clearance pathways that have yet to be pinned down.

The implications reach well beyond the laboratory. After Chernobyl, epidemiological studies documented a surge in thyroid cancer among people exposed as children to iodine-131 fallout, with the increase particularly pronounced among young girls — a pattern that has long suggested some combination of biological susceptibility and dosimetric difference. This study provides the first rigorous experimental evidence that the dose itself may differ systematically by sex and age, meaning that part of the observed cancer excess could reflect the fact that young females simply received more radiation to their thyroids from the same environmental exposure. The authors are careful to note that dosimetry alone cannot explain everything — biology at the cellular level certainly contributes — but the fourfold dose range they measured is far too large to ignore in risk models.

For nuclear medicine, the findings carry a more immediate practical message. Radioiodine therapy is prescribed to patients of both sexes and all ages, yet dosing protocols have historically been built on assumptions that may not hold uniformly across the population. If sex and age influence thyroid uptake and retention as strongly in humans as they do in rats, personalized dose planning — adjusting administered activity for patient sex and age — could improve therapeutic efficacy while sparing healthy tissue. The study also underscores the value of including both sexes and multiple age groups in preclinical radiopharmaceutical research, a practice that remains inconsistent across the field.

The Gothenburg team, whose work was supported by the Swedish Radiation Safety Authority, the Swedish Research Council, and the Swedish Cancer Society, among others, emphasizes that further research is needed to clarify the underlying biological and mechanistic drivers of the observed differences. Untangling whether hormonal status, thyroid growth dynamics, renal clearance, or other factors govern the sex- and age-dependent handling of iodine will be the next step. But the core conclusion stands on its own: when it comes to radioactive iodine, who you are and how old you are when exposure happens can change the dose your thyroid receives by a factor of four — a biological reality that both radiation oncologists and emergency planners can no longer afford to overlook.

Subject of Research: How sex and age at exposure influence the biodistribution and absorbed dose of radioactive iodine-131 in rats

Article Title: Sex and age at exposure influence 131I biodistribution and dosimetry in Sprague–Dawley rats

Article References: Schroff, A., Insulander Björk, K., Rassol, N., Johansson, J., Lundberg, T., Bakr, H., Andersson, M., Spetz, J., & Forssell-Aronsson, E. (2026). Sex and age at exposure influence 131I biodistribution and dosimetry in Sprague–Dawley rats. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00989-4

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00989-4

Keywords: radioiodine, iodine-131, thyroid, dosimetry, biodistribution, sex differences, Chernobyl, thyroid cancer, sodium-iodide symporter, radiation protection, Sprague-Dawley rats, nuclear medicine