LP-01
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BiP-20 is a branched ionizable phospholipid identified as a lead compound for efficient hepatic mRNA delivery.BiP-20 is a novel, efficient, and safe liver-targeted LNP delivery vehicle. With an ideal pKa of 6.56, it achieves highly efficient liver targeting and endosomal escape primarily through the ApoE/LDL-R pathway. It demonstrates exceptional performance in gene editing at very low doses: for CRISPR-Cas9-mediated editing of TTR, a 10 μg dose achieved ~64% efficiency, which is 8-fold higher than the clinical benchmark lipid LP-01. In Prime Editing targeting the PCSK9 gene, its efficiency (4.30%) also significantly surpassed that of MC3, SM102, and LPO1. Furthermore, it mediates a 5.9-fold increase in hepatic protein expression compared to MC3. Safety assessments indicate it does not induce liver function abnormalities, showing strong therapeutic potential.
| CAS No. | Not available |
| Chemical Name | BIP-20 |
| Synonyms | BIP20;BIP 20 |
| SMILES | CCCCCCCCCCC(CCCCCCCC)COP(NCCN(C)C)(OCC(CCCCCCCC)CCCCCCCCCC)=O |
| Formula | C44H93N2O3P |
| M.Wt | 729.2128 |
| Purity | ELSD-HPLC>95% |
| Storage | Pure form: −20 °C, 1 year; In solvent: −80 °C, 6 months; −20 °C, 1 month. Sealed and protected from light. |
| Shipping condition | Ships from Shanghai. Pure lipid is stable during ice-pack transport. |
| Publication | Jozić A, Le Roux C, Kim J, et al. In vivo endosomal escape assay identifies mechanisms for efficient hepatic LNP delivery. Nature Biotechnology. Published online March 11, 2026. doi:10.1038/s41587-026-03022-6. |
| Component | mol% | Role |
|---|---|---|
| BiP-20 | 50 | Ionizable lipid |
| DOPE | 10 | Helper phospholipid |
| Cholesterol | 38.5 | Sterol |
| DMPE-PEG2000 | 1.5 | PEG lipid |
| Reported total | 100 | Source values retained |
| Purpose | BiP-20 / DOPE / cholesterol / DMPE-PEG2000 (mol%) | Interpretation |
|---|---|---|
| Selected for subsequent studies | 50 / 10 / 38.5 / 1.5 | BiP20-R; selected because the higher-mean BiP-20-19 group was more variable. |
| Initial lipid screening | 35 / 16 / 46.5 / 2.5 | 10:1 ionizable lipid:mRNA w/w explicitly reported for screening. |
| Highest mean in formulation screen | 45 / 16 / 38.5 / 0.5 | BiP-20-19: 1.72-fold vs BiP20-R at 4 h, n=3, p=0.0216. |
Main PDF pp.2–4,12; SI Fig.S5e, PDF p.7. Component order is kept identical across rows.
| Helper lipid | DLS diameter (nm) | PDI | mRNA EE (%) | Reporter result |
|---|---|---|---|---|
| DOPE | ~42 | ~0.14 | ~98 | Stronger liver expression; n=3 mice |
| DSPC | ~40 | ~0.17 | ~98 | Lower reporter expression; n=2 mice |
SI Fig.S4, PDF p.6 (printed p.5). Diameter, PDI and EE are approximate visual readings of plotted means, not tabulated values. These are helper-comparison LNPs; do not transfer these properties to the final BiP20-R editing formulation. Fig.S4 does not restate full composition.
| Cargo / endpoint | Dose and readout | BiP-20 result | Benchmark / interpretation |
|---|---|---|---|
| Cas9 + sgTTR / genomic indels | 2 µg total RNA; day 7; n=4 | ~20% | Genomic sequencing; separate from serum TTR protein |
| Cas9 + sgTTR / genomic indels | 10 µg total RNA; day 7; n=4 | ~64% | LP01 ~30 µg for a comparable editing level |
| Cas9 + sgTTR / serum TTR | 1 µg total RNA; day 7; n=4 | ~50% reduction; p=0.0093 | SI reports up to 40% indels; not a mean editing percentage |
| PEmax + pegRNA + ngRNA / TTAC insertion | Reported 50 µg/mouse; day 7; n=4 | 4.30% | SM102 3.33%; MC3 1.33%; LP01 0.1225% |
Main Fig.1h–j and text, PDF pp.3–4; SI Figs.S7–S8, PDF pp.9–10. Prime-editing significance was established vs MC3 and LP01, not vs SM102. Main p.4 calls the 50 µg dose both total RNA and “total mRNA”; obtain clarification before reproducing component masses.
The microfluidic method uses ethanol-solubilized lipids and pH-4 citrate RNA, aqueous:ethanol 3:1 v/v, and 12 mL/min total flow. The 10:1 mass ratio is explicitly tied to initial lipid:mRNA screening. No N/P ratio or separate selected-formulation ionizable-lipid:total-editing-RNA ratio is given.
Main methods are reported laboratory conditions, not a validated product-specific manufacturing specification. · Main PDF pp.12–13LysoBC yielded approximately 8% at 30 min and 6% at 1 h. It compares DNA barcode reads in non-HA-bound flow-through against flow-through plus isolated HA-tagged endolysosomal reads. The authors treat this as a proxy for extra-lysosomal localization; it does not prove that every counted barcode supports productive delivery.
5 µg modified DNA barcode, IV; LysoTag mice; n=4. Cargo and assay differ from mRNA expression and editing studies. · Main Fig.2j, PDF pp.5–6; qualification p.7; SI Fig.S10, PDF p.12ApoE knockout nearly eliminated liver reporter signal, while LDL-R knockout substantially reduced it. These experiments support ApoE-dependent uptake with a contribution from LDL-R and potentially other receptors.
C57BL/6, ApoE−/− and LDL-R−/− cohorts, n=3; reporter expression at 4 h and 24 h. This is an uptake-dependence result, not a measured receptor-specific endosomal escape rate. · Main PDF p.4; SI Fig.S6, PDF p.8At 50 µg total RNA per mouse and 24 h after IV retro-orbital administration, ALT and AST were comparable to untreated controls. BiP-20 did not significantly increase IL-6; TNFα was below the assay detection limit.
Single-dose serum endpoints only. ALT/AST n=4; IL-6 treated groups n=4, untreated n=3. No claim of clinical, repeat-dose or long-term safety. · Main Safety profile, PDF p.7; SI Fig.S11, PDF p.13The SI identifies BiP-20 as O,O-bis(2-octyldodecyl)-N-(2-(dimethylamino)ethyl)phosphoramidate, formula C44H93N2O3P, MW 729.21 g/mol. It has two saturated branched C20 tails and a dimethylaminoethyl head attached through a phosphoramidate N–H.
Identity is consistent with the existing DC68021 SMILES and formula; product specifications are retained. The SI reports synthesis and characterization, not a DC Chemicals batch COA. · Main Fig.1c, PDF p.3; SI PDF p.51 (printed p.50); BiP-20 NMR/HRMS SI PDF pp.137–139The product molecular weight is prefilled when available and remains editable. Confirm solvent compatibility and solubility before preparation.
Solvent volumes update from the molecular weight above.
| Mass | 1 mM | 5 mM | 10 mM |
|---|---|---|---|
| 10 mg | 13.7134 mL | 2.7427 mL | 1.3713 mL |
| 25 mg | 34.2835 mL | 6.8567 mL | 3.4284 mL |
| 50 mg | 68.5671 mL | 13.7134 mL | 6.8567 mL |
| 100 mg | 137.1342 mL | 27.4268 mL | 13.7134 mL |
| 250 mg | 342.8355 mL | 68.5671 mL | 34.2835 mL |
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