Recombinant ferritins for multimodal nanomedicine

Figures & data

Figure 1. Recombinant ferritin induces high levels of neutralising antibodies.

Figure 2. Long-term efficacy of ferritin nanovaccine.

Figure 3. Pt-ferritin develops peroxidase activity to improve the tumour hypoxic microenvironment pO₂, thus making it more sensitive to chemotherapy and radiotherapy.

Figure 4. Thermal stability of recombinant ferritin nanozymes.

Figure 5. Targeted inductions of cancer cell apoptosis by recombinant ferritin.

Figure 6. Recombinant ferritin delivery of Cyt c induces in APLs cell apoptosis and nanodrug-0504 inhibits proliferation of pancreatic cancer cells.

Figure 7. Recombinant ferritin in bone imaging.

Table 1. A summary of recombinant ferritin in multimodal nanomedicine.

Ferritin carrier	Expression system	Surface modification	Targeting receptor	Major utilisation	References
H. pylori	HEK293T	RBD and Ftn spaced by a SSGGASVLA linker	S protein	viral vaccine	Kim et al.^13
Thermococcus furiosus Ftn	–	–	GRP78	targeted therapy for Hcc	Jiang et al.^20
–	HepG2	Covalent attachment of HFtn to N-PCNSs was performed using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS)	–	artificial enzymes	Fan et al.^21
H. pylori	HEK293F	S protein and Ftn spaced by an SGG linker	S protein	SARS-CoV-2 vaccine	Powell et al.^24
Rat H-chain	HEK293F CHO	–	EV71	RSV vaccine	Wang et al.^34
Human H-chain	E. coli	Loading Fe^2+ into the cavities of HFtn nanocages through the iron ion channel on the surface of HFtn nanocage	–	artificial enzyme	Wang et al.^49
Pyrococcus furiosus Ftn	BL21-CodonPlus (DE3)-RIL	–	–	artificial enzymes	Peskova et al.^51
H. pylori-bullfrog hybrid	HEK293F	HA and Ftn spaced by an SG linker	RBD of HA	viral vaccine	Kalathiya et al.^37
H. pylori	HEK-293T	Ftn-coupled HA sequences	YaH3F, YaH4F, and YaH5F	CDV vaccine	Wang et al.^39
–	Drosophila S2 cell	Trimeric SARS-CoV-2 S protein devoid of transmembrane domain	S protein	viral vaccine	Lai et al.^25
H. pylori bullfrog Ftn	HEK293F	gp350 and Ftn spaced by an (SG3)2 linker	gp350	EBV vaccine	Kanekiyo et al.^27
H. pylori	HEK293F	CD5 leader sequence and a SGG spacer were fused to the gene fragment encoding Ftn	HA	H1N1 vaccine	Kanekiyo et al.^28
T. ni L- and H-chains	HEK293F	gp140 and Ftn spaced by a (GS)5 linker	gp140	HIV-1 vaccine	Georgiev et al.^29
H. pylori bullfrog Ftn	BL21	N-terminal fusion of alpha-hemolysin with Ftn CDS	alpha-hemolysin	Staphylococcus aureus vaccine	Wei et al.^31
Rat H-chain	BL21(DE3)	SpyCatcher fused to C-terminal of preS1; SpyTag and Ftn spaced by a (G4S)3 linker	preS1 of HBV	HBV vaccine	Wang et al.^32
H. pylori (N19Q)^2	–	–	TLR4/NF-κB	DC-based vaccine	Qu et al.^33
Human HFn (Prussian blue PB-modifified)	–	Recombination of encapsulated PB after Ftn depolymerisation	–	breast cancer targeted therapy	Li et al.^77
Human HFn	–	–	TfR1	breast cancer targeted therapy	Li et al.^66
Human H-chain	–	tLyP-1 was fused to the N-terminal end of human HFtn, encapsulating the PTX molecule into HFtn to form tLyP-1-HFtn-PTX	TfR1	breast cancer targeted therapy	Ma et al.^67
Human H-chain	–	HFtn - Curcumin	–	TNBC therapy	Pandolfi et al.^68
humanized archaeal Ftn (HumFt)	E. Coli	–	–	deliver cyt C	Macone et al.^61
Human H-chain	–	folic acid	folic acid receptor	deliver folic acid	Zhen et al.^79
Human HFtn	–	–	–	deliver genz-644282	Falvo et al.^64
Human Ftn	–	siRNA	PBMCs	genetic silence	Li et al.^81
–	BL21 (DE3)	Osteoblast and hydroxyapatite binding to HFtn by a GSS linker	OB-Ftn and HA-Ftn	bone disease imaging	Kim et al.^89
Human HFn (CDs modifified)	–	–	–	beast cancer imaging	Yao et al.^90
–	HEK-293T	–	–	cerebral infarct imaging	Huang et al.^95
Ftn-like protein, 7 A,	–	Encapsulated Au- NCs	–	methylmercury imaging	Lv et al.^96

Kim Y-I, Kim D, Yu K-M, Seo HD, Lee S-A, Casel MAB, Jang S-G, Kim S, Jung WRam, Lai C-J, et al. Development of spike receptor-binding domain nanoparticles as a vaccine candidate against SARS-CoV-2 infection in ferrets. Mbio. 2021;12(2):e00230–21.

 PubMed Web of Science ®Google Scholar

Jiang B, Zhang R, Zhang J, Hou Y, Chen X, Zhou M, Tian X, Hao C, Fan K, Yan X, et al. GRP78-targeted ferritin nanocaged ultra-high dose of doxorubicin for hepatocellular carcinoma therapy. Theranostics. 2019;9(8):2167–2182.

 PubMed Web of Science ®Google Scholar

Fan K, Xi J, Fan L, Wang P, Zhu C, Tang Y, Xu X, Liang M, Jiang B, Yan X, et al. In vivo guiding nitrogen-doped carbon nanozyme for tumor catalytic therapy. Nat Commun. 2018;9(1):1440.

 PubMedGoogle Scholar

Powell AE, Zhang K, Sanyal M, Tang S, Weidenbacher PA, Li S, Pham TD, Pak JE, Chiu W, Kim PS, et al. A single immunization with spike-functionalized ferritin vaccines elicits neutralizing antibody responses against SARS-CoV-2 in mice. ACS Cent Sci. 2021;7(1):183–199.

 PubMed Web of Science ®Google Scholar

Wang Z, Xu L, Yu H, Lv P, Lei Z, Zeng Y, Liu G, Cheng T. Ferritin nanocage-based antigen delivery nanoplatforms: epitope engineering for peptide vaccine design. Biomater Sci. 2019;7(5):1794–1800.

 PubMed Web of Science ®Google Scholar

Wang T, He J, Duan D, Jiang B, Wang P, Fan K, Liang M, Yan X. Bioengineered magnetoferritin nanozymes for pathological identification of high-risk and ruptured atherosclerotic plaques in humans. Nano Res. 2019;12(4):863–868.

 Web of Science ®Google Scholar

Peskova M, Ilkovics L, Hynek D, Dostalova S, Sanchez-Carnerero EM, Remes M, Heger Z, Pekarik V. Detergent-modified catalytic and enzymomimetic activity of silver and palladium nanoparticles biotemplated by Pyrococcus furiosus ferritin. J Colloid Interface Sci. 2019;537:20–27.

 PubMed Web of Science ®Google Scholar

Kalathiya U, Padariya M, Fahraeus R, Chakraborti S, Hupp TR. Multivalent display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to nanomaterial, protein ferritin nanocages. Biomolecules. 2021;11(2):297.

 PubMed Web of Science ®Google Scholar

Wang B, Li S, Qiao Y, Fu Y, Nie J, Jiang S, Yao X, Pan Y, Zhao L, Wu C, et al. Self-assembling ferritin nanoparticles coupled with linear sequences from canine distemper virus haemagglutinin protein elicit robust immune responses. J Nanobiotechnol. 2022;20(1):32.

 PubMed Web of Science ®Google Scholar

Lai C-Y, To A, Wong TAS, et al. Recombinant protein subunit SARS-CoV-2 vaccines formulated with CoVaccine HT adjuvant induce broad, Th1 biased, humoral and cellular immune responses in mice. bioRxiv. 2021

 Google Scholar

Kanekiyo M, Bu W, Joyce MG, Meng G, Whittle JRR, Baxa U, Yamamoto T, Narpala S, Todd J-P, Rao SS, et al. Rational design of an epstein-barr virus vaccine targeting the receptor-binding site. Cell. 2015;162(5):1090–1100.

 PubMed Web of Science ®Google Scholar

Kanekiyo M, Wei C-J, Yassine HM, McTamney PM, Boyington JC, Whittle JRR, Rao SS, Kong W-P, Wang L, Nabel GJ, et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature. 2013;499(7456):102–106.

 PubMed Web of Science ®Google Scholar

Georgiev IS, Joyce MG, Chen RE, Leung K, McKee K, Druz A, Van Galen JG, Kanekiyo M, Tsybovsky Y, Yang ES, et al. Two-component ferritin nanoparticles for multimerization of diverse trimeric antigens. ACS Infect Dis. 2018;4(5):788–796.

 PubMed Web of Science ®Google Scholar

Wei J, Cheng X, Zhang Y, Gao C, Wang Y, Peng Q, Luo P, Yang L, Zou Q, Zeng H, et al. Identification and application of a neutralizing epitope within alpha-hemolysin using human serum antibodies elicited by vaccination. Mol Immunol. 2021;135:45–52.

 PubMed Web of Science ®Google Scholar

Wang W, Zhou X, Bian Y, Wang S, Chai Q, Guo Z, Wang Z, Zhu P, Peng H, Yan X, et al. Dual-targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic hepatitis B. Nat Nanotechnol. 2020;15(5):406–416.

 PubMed Web of Science ®Google Scholar

Qu Z, Guo Y, Li M, Cao C, Wang J, Gao M. Recombinant ferritin nanoparticles can induce dendritic cell maturation through TLR4/NF-kappaB pathway. Biotechnol Lett. 2020;42(12):2489–2500.

 PubMed Web of Science ®Google Scholar

Li H, Zhang W, Ding L, Li XW, Wu Y, Tang JH. Prussian blue-modified ferritin nanoparticles for effective tumor chemo-photothermal combination therapy via enhancing reactive oxygen species production. J Biomater Appl. 2019;33(9):1202–1213.

 PubMed Web of Science ®Google Scholar

Li R, Ma Y, Dong Y, Zhao Z, You C, Huang S, Li X, Wang F, Zhang Y. Novel Paclitaxel-Loaded Nanoparticles Based on Human H Chain Ferritin for Tumor-Targeted Delivery. ACS Biomater Sci Eng. 2019;5(12):6645–6654.

 PubMed Web of Science ®Google Scholar

Ma Y, Li R, Dong Y, You C, Huang S, Li X, Wang F, Zhang Y. tLyP-1 peptide functionalized human H chain ferritin for targeted delivery of paclitaxel. Int J Nanomedicine. 2021;16:789–802.

 PubMed Web of Science ®Google Scholar

Pandolfi L, Bellini M, Vanna R, Morasso C, Zago A, Carcano S, Avvakumova S, Bertolini JA, Rizzuto MA, Colombo M, et al. H-ferritin enriches the curcumin uptake and improves the therapeutic efficacy in triple negative breast cancer cells. Biomacromolecules. 2017;18(10):3318–3330.

 PubMed Web of Science ®Google Scholar

Macone A, Masciarelli S, Palombarini F, Quaglio D, Boffi A, Trabuco MC, Baiocco P, Fazi F, Bonamore A. Ferritin nanovehicle for targeted delivery of cytochrome C to cancer cells. Sci Rep. 2019;9(1):11749

 PubMedGoogle Scholar

Zhen ZP, Tang W, Zhang WZ, Xie J. Folic acid conjugated ferritins as photosensitizer carriers for photodynamic therapy. Nanoscale. 2015;7(23):10330–10333.

 PubMed Web of Science ®Google Scholar

Falvo E, Arcovito A, Conti G, Cipolla G, Pitea M, Morea V, Damiani V, Sala G, Fracasso G, Ceci P, et al. Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy. Pharmaceutics. 2020;12(10):992.

 PubMed Web of Science ®Google Scholar

Li L, Muñoz-Culla M, Carmona U, Lopez MP, Yang F, Trigueros C, Otaegui D, Zhang L, Knez M. Ferritin-mediated siRNA delivery and gene silencing in human tumor and primary cells. Biomaterials. 2016;98:143–151.

 PubMed Web of Science ®Google Scholar

Kim JW, Lee KK, Park KW, Kim M, Lee CS. Genetically modified ferritin nanoparticles with bone-targeting peptides for bone imaging. IJMS. 2021;22(9):4854.

 Google Scholar

Yao HC, Zhao WW, Zhang SG, Guo XF, Li Y, Du B. Dual-functional carbon dot-labeled heavy-chain ferritin for self-targeting bio-imaging and chemo-photodynamic therapy. J Mater Chem B. 2018;6(19):3107–3115.

 PubMed Web of Science ®Google Scholar

Huang XL, Xue Y, Wu JL, Zhan Q, Zhao JM. MRI tracking of SPIO- and Fth1-labeled bone marrow mesenchymal stromal cell transplantation for treatment of stroke. Contrast Media Mol Imaging . 2019;2019:1–10.

 Web of Science ®Google Scholar

Lv CY, Yin SH, Zhang XQ, Hu JW, Zhang T, Zhao GH. 16-Mer ferritin-like protein templated gold nanoclusters for bioimaging detection of methylmercury in the brain of living mice. Anal Chim Acta. 2020;1127:149–155.

 PubMed Web of Science ®Google Scholar