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- EMDB-62216: Bioengineered protein nanocarrier facilitating siRNA escape from ... -

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Basic information

Entry
Database: EMDB / ID: EMD-62216
TitleBioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma
Map data
Sample
  • Organelle or cellular component: human ferritin heavy chain mutant
    • Protein or peptide: Ferritin heavy chain, N-terminally processed
KeywordsBioengineered ferritin / Lysosomal escape / siRNA delivery / Glioblastoma targeted therapy / EGFR and TERT / METAL TRANSPORT
Function / homology
Function and homology information


iron ion sequestering activity / ferritin complex / negative regulation of ferroptosis / Scavenging by Class A Receptors / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / negative regulation of fibroblast proliferation / ferric iron binding ...iron ion sequestering activity / ferritin complex / negative regulation of ferroptosis / Scavenging by Class A Receptors / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / negative regulation of fibroblast proliferation / ferric iron binding / autophagosome / Iron uptake and transport / ferrous iron binding / tertiary granule lumen / iron ion transport / ficolin-1-rich granule lumen / intracellular iron ion homeostasis / immune response / iron ion binding / negative regulation of cell population proliferation / Neutrophil degranulation / extracellular exosome / extracellular region / identical protein binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Ferritin iron-binding regions signature 1. / Ferritin iron-binding regions signature 2. / Ferritin, conserved site / Ferritin / Ferritin-like diiron domain / Ferritin-like diiron domain profile. / Ferritin/DPS protein domain / Ferritin-like domain / Ferritin-like / Ferritin-like superfamily
Similarity search - Domain/homology
Ferritin heavy chain
Similarity search - Component
Biological speciesHomo sapiens (Human) (human) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 1.73 Å
AuthorsChen X / Fan K
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2021YFA1201102 China
CitationJournal: Sci Adv / Year: 2025
Title: Bioengineered protein nanocarrier facilitating siRNA escape from lysosomes for targeted RNAi therapy in glioblastoma.
Authors: Yiliang Jin / Baoli Zhang / Jianru Li / Zhenxi Guo / Chen Zhang / Xuehui Chen / Long Ma / Zhuoran Wang / Haiyin Yang / Yong Li / Yuhua Weng / Yuanyu Huang / Xiyun Yan / Kelong Fan /
Abstract: RNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This ...RNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This challenge is especially prominent in glioblastoma (GBM) therapy, necessitating the penetration of the blood-brain barrier (BBB). Leveraging the intrinsic tumor-targeting and BBB traversing capability of human H-ferritin, we designed a series of ferritin variants with positively charged cavity and truncated carboxyl terminus, termed tHFn(+). These nanocarriers respond to weak acid and disassemble in endosomal compartments, exposing the internal positive charges to facilitate the lysosomal escape of loaded small interfering RNA (siRNA). Functioning as universal siRNA nanocarriers, tHFn(+) significantly enhanced the uptake of different siRNAs and suppressed gene expressions associated with GBM progression. Furthermore, tHFn(+) traversed the BBB and targeted glioma in vivo by binding to its receptors (e.g., transferrin receptor 1). tHFn(+)-delivered siRNAs exhibited exceptional therapeutic effects against glioma in vivo, advancing RNAi therapeutics beyond GBM for the treatment of various diseases.
History
DepositionOct 30, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62216.png

Downloads & links

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Map

FileDownload / File: emd_62216.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.53 Å/pix.
x 384 pix.
= 203.52 Å		0.53 Å/pix.
x 384 pix.
= 203.52 Å		0.53 Å/pix.
x 384 pix.
= 203.52 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.53 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.151
Minimum - Maximum-0.43807912 - 0.8635695
Average (Standard dev.)0.001765175 (±0.040083796)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 203.51999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_62216_msk_1.map
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Half map: #2

Fileemd_62216_half_map_1.map
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Half map: #1

Fileemd_62216_half_map_2.map
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Sample components

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Entire : human ferritin heavy chain mutant

EntireName: human ferritin heavy chain mutant
Components
  • Organelle or cellular component: human ferritin heavy chain mutant
    • Protein or peptide: Ferritin heavy chain, N-terminally processed

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Supramolecule #1: human ferritin heavy chain mutant

SupramoleculeName: human ferritin heavy chain mutant / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all / Details: 1-159, E61K/E64R/E140K/E147K
Source (natural)Organism: Homo sapiens (Human) (human)
Molecular weightTheoretical: 18.6 kDa/nm

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Macromolecule #1: Ferritin heavy chain, N-terminally processed

MacromoleculeName: Ferritin heavy chain, N-terminally processed / type: protein_or_peptide / ID: 1 / Number of copies: 24 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.673164 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
TTASTSQVRQ NYHQDSEAAI NRQINLELYA SYVYLSMSYY FDRDDVALKN FAKYFLHQSH KERRHAEKLM KLQNQRGGRI FLQDIKKPD CDDWESGLNA MECALHLEKN VNQSLLELHK LATDKNDPHL CDFIETHYLN KQVKAIKKLG DHVTNLRKMG

UniProtKB: Ferritin heavy chain

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8 / Details: 20 mM Tris, pH8.0, 50 mM NaCl
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 0.7000000000000001 µm / Nominal defocus min: 0.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1725802
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4yo8


Details: Human ferritin heavy chain structure 4Y08 was used as the initial model, then the symmetry F432 was applied and thus obtained a homo 24-mer spherical structure as the startup model.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 1.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 966873
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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