ArticleBioconjugate chemistry2026
RNA Size and Structure Modulate the Apparent pKa of Ionizable Lipid Nanoparticles.
Article in Bioconjugate chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ionizable lipid nanoparticles (LNPs) underpin today's RNA medicines by shielding nucleic acids in the bloodstream and transforming into membrane-active cationic nanoparticles inside acidifying endosomes. This behavior critically depends on the apparent pKa of LNPs, which can be tuned by altering the chemistry of lipids/lipidoids and the ratios of helper lipids. However, formulators typically assume that different RNA payloads exert identical effects on LNP ionization. In this study, we challenge this assumption and quantify how RNA modulates LNP pKa. LNP formulations with different ionizable lipidoids (SM-102, cKK-E12, ALC-0315, 306Oi10, XMAN6, and C12-200) were used to encapsulate various RNA cargos, which ranged from 21-nt to 4.5-kb mRNAs. Apparent pKa values were determined using a TNS fluorescence titration assay. RNA payload size impacted the apparent pKa of the LNPs by 0.1-0.5 pH units, the direction and magnitude of the change being dependent on the structure of the ionizable lipidoid. Moreover, same-length 21-nt siRNA and miRNA cargos produced a 0.15 pH-unit difference in XMAN6 LNPs, indicating that RNA structural features can modulate apparent pKa independently of payload size. With the monoamine lipidoid SM-102, short RNAs lowered the apparent pKa relative to mRNA-loaded particles, whereas the multiamine lipidoids cKK-E12 and XMAN6 exhibited a monotonic decrease in apparent pKa as RNA length increased, plateauing at ∼1.9 kb. The most pronounced discrepancies between apparent pKa values of lipidoid particles and corresponding LNPs (of ≤0.5 pH units) were observed with the triamine lipidoid XMAN6, pointing to a role of amino group multiplicity in the modulation of apparent pKa. These findings demonstrate that RNA payload size is an underappreciated lever for tuning LNP ionization behavior and that considering RNA payload size when conducting lipid/lipidoid library screens could enhance the development of future RNA-based therapeutics.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.