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PA97MD101
Formulation & Performance
Literature LNP formulation
| Components / mol% | PA97MD101 / DSPC / Cholesterol / PEG-DMG (PEG2000) = 50 / 10 / 38.5 / 1.5 (total 100%) |
| N/P ratio | Not reported |
| Preparation | Microfluidic mixing; ethanol 3 mL/min + aqueous phase 9 mL/min; total flow 12 mL/min |
| Aqueous phase | 10 mM sodium citrate, pH 4.5 |
| Post-processing | At least three 30 kDa centrifugal-filter wash cycles, then 0.22 μm filtration; adjusted to 1 mg/mL total lipid; formulated LNPs stored at 4°C until use |
| Apparent LNP pKa | 6.85 (TNS fluorescence titration) |
| mRNA encapsulation | 91.19 ± 0.58% SD; n = 3 independent samples (RiboGreen assay) |
| Mass ratio | 40:1 lipid:mRNA is specified for the in vitro screen; it is not an N/P ratio and is not assigned here to the in vivo experiments |
Main Methods pp. 10-11; Supplementary Fig. 25, p. 26. Exact particle size and PDI are not transcribed from plotted figures.
Reference [1]: Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Exact source locations are given above.
Component molecular weights and calculated amounts
Main Methods pp. 10–11; catalog MW convention for PEG-DMG = 2507.
| Component | Molecular weight | Molar parts | Normalized mol% | Amount (µmol) | Weight (mg) |
|---|---|---|---|---|---|
| PA97MD101 | 50.000 | 71.5604 | 62.0042 | ||
| DSPC | 10.000 | 14.3121 | 11.3087 | ||
| Cholesterol | 38.500 | 55.1015 | 21.3050 | ||
| PEG-DMG (PEG2000) | 1.500 | 2.1468 | 5.3821 |
Calculated total: 100.0000 mg lipid.
Calculated catalog planning quantities; RNA, solvent and process loss are excluded. DMG-PEG2000 uses 2507. Component mass = total lipid mass × molar parts × molecular weight / sum(parts × molecular weight). This conversion does not infer N/P.
Hepatic luciferase expression
| Cargo | Fluc mRNA |
| Route | Intravenous, tail vein |
| Dose | 0.1 mg/kg mRNA, single injection |
| Model | C57BL/6 mice, 6-8 weeks; n=3/group |
| Readout time | 6 h |
Hepatic Fluc expression: Approximately 4-fold higher than SM-102 (author-reported approximation).
Main Results p.6 and Discussion p.8; Fig.5c-e; Methods p.10. Comparator: SM-102, matched cargo/dose/route/time.
Cropped from Zhang et al., Fig. 5c-d; labels and axes retained. CC BY 4.0.
Reference [1]: Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Exact source locations are given above.
Cre-dependent liver recombination
| Cargo | Cre mRNA |
| Route | Intravenous, tail vein |
| Dose | 0.25 mg/kg mRNA, single injection |
| Model | mTmG reporter mice; n=3/group |
| Readout time | Day 3 |
Liver-level Cre-dependent functional output: Approximately 6.75-fold higher liver-level Cre-dependent recombination reported in Discussion; fluorescence and LoxP qPCR support functional delivery.
Main Discussion p.8; Fig.5g-j; Methods pp.11-12; SI Figs.34-42. Comparator: SM-102.
Cell-population-resolved output: Greater EGFP activation in CD31-/CD45- hepatocyte-enriched cells; not hepatocyte-exclusive or proof of receptor-specific targeting.
Main Results p.6; Fig.5i-j; SI Fig.41 (p.41). Comparator: SM-102.
Cropped from Zhang et al., Fig. 5j. EGFP activation measures functional delivery and recombination, not nanoparticle uptake alone. CC BY 4.0.
Reference [1]: Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Exact source locations are given above.
Cas9/sgTtr delivery and TTR suppression
| Cargo | Cas9 mRNA + sgTtr, 5:1 mass ratio |
| Route | Intravenous, tail vein |
| Dose | Per injection: Cas9 mRNA 0.25 mg/kg plus sgRNA 0.05 mg/kg; two consecutive daily injections. sgRNA dose and 0.30 mg/kg total RNA per injection are calculated from 5:1. |
| Model | C57BL/6 mice; n=3/group |
| Readout time | Day 7 after first injection |
Ttr transcript and serum TTR suppression: Lower hepatic Ttr FISH signal and serum TTR than SM-102; transcript/protein endpoints, not a measured genomic editing percentage.
Main Fig.6c-e, Results p.6, Methods p.11; SI Fig.46. Comparator: SM-102; PBS; Methods also describe a Cas9-only control.
Cropped from Zhang et al., Fig. 6d-f; hEPO in panel f belongs to the separate experiment below. CC BY 4.0.
Reference [1]: Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Exact source locations are given above.
Secreted hEPO expression
| Cargo | hEPO mRNA |
| Route | Intravenous, tail vein |
| Dose | 0.25 mg/kg mRNA |
| Model | C57BL/6 mice; n=3/group |
| Readout time | 24 h |
Serum hEPO: Higher serum hEPO than SM-102 and PA86MD16; exact concentrations not transcribed from graph.
Main Fig.6f, Results p.6, Methods pp.10-11. Comparator: SM-102 and PA86MD16.
Reference [1]: Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Exact source locations are given above.
Mechanistic and tolerability observations
PA97MD101 and PA86MD16 showed reduced lysosomal colocalization in HeLa cells. Acidic-pH hemolysis and lipid-mixing assays support pH-dependent membrane activity. These observations are compatible with improved intracellular release; they do not demonstrate a specific hepatocyte receptor mechanism.
The study found no overt injury in examined acute histology and lower cytokine responses for PA97MD101 in the plotted comparisons. This does not establish chronic or clinical safety. The cytokine-specific dose and cargo are not fully resolved in the supplied methods.
Main Fig. 4 and Fig. 6g-m; Supplementary Figs. 23-25 and 48-49. Animal results generally n = 3 per group.
Reference [1]: Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Exact source locations are given above.
References for formulation & performance
- Zhang Z, Ren Y, Kong D, et al. Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Nature Communications (2026), Article in Press. doi:10.1038/s41467-026-78635-1. Main Methods pp. 10–11; Fig. 5 (Fluc/Cre); Fig. 6 (Cas9/sgTtr, hEPO and acute observations). Supplementary Fig. 22, pp. 23–24 (identity); Fig. 25, p. 26 (pKa and encapsulation). Page numbers refer to the supplied article-in-press PDF and supplementary PDF. Supplementary information is accessible through the publisher article page.
- DC Chemicals. 1,2-DSPC (DC57005). Molecular weight 790.15 g/mol, rounded from the product specification.
- DC Chemicals. Cholesterol (DCD-041). Molecular weight 386.65 g/mol.
- DC Chemicals. DMG-PEG2000 (DC40169). Confirm the complete conjugate average molecular weight from the batch documentation; no fixed value is preselected in this calculator.
DC Chemicals component specifications checked 14 October 2026. The cited paper provides the formulation and performance evidence; product links identify corresponding catalog components.
Published study figures
Original publication figures illustrating the cited formulation and biological results. Select an image to view it at full size.
Figure 5c-d — Whole-body and hepatic luciferase expression
Whole-body and hepatic luciferase expression. C57BL/6 mice; Fluc mRNA 0.1 mg/kg intravenously; 6 h; n=3/group.
Zhang Z, Ren Y, Kong D, et al. (2026). Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Original article / figure · CC BY 4.0. Existing published-site crop of Figure 5c-d; graph labels, axes and data retained.
Figure 5j — Cre-dependent reporter response resolved by liver cell population
Cre-dependent reporter response resolved by liver cell population. mTmG mice; Cre mRNA 0.25 mg/kg intravenously; day 3; n=3/group.
Zhang Z, Ren Y, Kong D, et al. (2026). Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Original article / figure · CC BY 4.0. Existing published-site crop of Figure 5j; functional recombination, not uptake alone.
Figure 6d-f — Hepatic Ttr transcript signal, serum TTR and separate hEPO expression results
Hepatic Ttr transcript signal, serum TTR and separate hEPO expression results. Panels d-e: Cas9/sgTtr study; panel f: separate hEPO-mRNA experiment.
Zhang Z, Ren Y, Kong D, et al. (2026). Interpretable AI-guided discovery of degradable ionizable lipids with enhanced hepatic mRNA delivery in vivo. Original article / figure · CC BY 4.0. Existing published-site crop of Figure 6d-f. Panel f is a separate hEPO experiment and must not be interpreted as a TTR-editing outcome.