Divergent Delivery and Expression Kinetics of Lipid and Polymeric Nanoparticles across mRNA Modalities
Bibliographic record
Abstract
Messenger ribonucleic acid (mRNA)-based therapies, including conventional linear mRNA (linRNA), circular RNA (circRNA), and self-amplifying RNA (saRNA), are being developed not only for vaccination but also for protein replacement, gene editing, and regenerative medicine. However, these mRNA modalities differ in structure and function, and their interactions with current non-viral delivery systems influence their therapeutic efficacy. Here, the in vivo expression kinetics of linRNA, circRNA, and saRNA delivered via lipid nanoparticles (LNPs) or bioreducible poly(cystamine bisacrylamide-co-4-amino-1-butanol) (pABOL) polymer are systematically evaluated. At 0.5 µg, Venezuelan equine encephalitis virus (VEEV)-based saRNA resulted in higher total luciferase expression than 5 µg of linRNA or circRNA highlighting its superior potency. LNPs significantly enhanced expression of non-amplifying mRNAs compared to pABOL, whereas pABOL delivery of saRNA yielded a ∼2-fold improvement over LNPs. Furthermore, saRNAs derived from New World alphaviruses expressed 2-6 times more protein than Old World saRNAs when delivered with LNPs; these differences are not observed with pABOL. These findings demonstrate that mRNA modality, saRNA genotype, and delivery platform interact to determine therapeutic protein output. This study provides actionable insights for optimizing mRNA-based therapeutics across diverse clinical applications.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".