Table 1.

Detargeting and retargeting strategies with representative studies.

Strategy	Examples	References
a. Selective Detargeting And Retargeting Towards Specific Receptors/Cells.
Detargeting of AdV structural proteins
Detargeting in Hexon
Insertion of lysine in hexon	Liver detargeting	[60]
Insertion of targeting peptides	Skeletal muscle cells, liver detargeting	[64,65,76,77,78,79]
Insertion of large universal acceptor proteins (BAP)	Liver detargeting	[80]
HVR swap	Liver detargeting, breast cancer, immune evasion	[57,59,61]
Drugs (warfarin, Snake venom protein X-Bp)	Liver detargeting	[62,63]
Hexon and pIX	Liver detargeting, HCC, ovarian carcinoma, melanoma	[81,82,83]
Detargeting of Fiber
Modified HI-loop Modified AB-loop Insertion of proteins or universal acceptors	neuronal cells, brain endothelial cells, vascular endothelial cells, prostate cancer, lung cancer, pancreatic cancer, muscle cells, colorectal cancer	[66,67,85,86,87,88,89,90,91,92,93,94,95,96,97] [55,100] [87,88,98,99,101,102,103,104,105,106,107,108,109,110,111,112,113,114]
Infectivity Selective Screening for Specific Targeting: Strategies and Importance
Phage display and other screening: Insertion of selected peptides into AdV proteins	Liver detargeting, neuronal cells, brain endothelial cells, vascular endothelial cells, prostate cancer, lung cancer, pancreatic cancer, muscle cells, colorectal cancer	[79,121]
Adenovirus-library-based screening: Direct modification of AdV libraries.	Liver detargeting, pancreatic cancer, colorectal cancer.	[55,100]
Retargeting of AdV by Affinity Modifiers
Antibody–antibody-based bridging molecules	Anti-AdV protein conjugated to VEGFR, TIE-2, integrins, EPCAM, EGFR, HER2, Endoglin, HMWMAA	[127,128,129,130,131,132]
Antibody–ligand-based bridging molecules	anti-AdV protein conjugated to Folate, TNFa, IGF1, EGF	[133,134]
Peptide–antibody-based bridging molecules	p75 neurotropin receptor on hepatic stellate cells	[135]
Soluble receptors conjugated to ligands (sCAR, FX)	EGF, anti-Cd40 ScFv, ApoE ligand, anti-ErbB2, anti-CEA, Polysialyc-acid (PSA), CXCL12	[136,137,138,139,140,141,142,143,144,145]
BiTE, Leucine-zipper-based linkers	CD44v6, anti-B-cell maturation antigen, FR-α, EGFR, EpCAM, carcinoembryonic antigen, CD40	[147,148,149,150,151,152,153,154]
b. Selective Expression of Effectors (Inhibitors/Enhancers) in Specific Cells.
Protein-based effectors	Interferons, GM-CSF, IL12, CD40L, CTLA4	[156,157,158,159,160,161,162,163,164,165,166,167,168,170]
Nucleic-acid-based effectors.	Liver detargeting, miR122, miR145, miR148, miR21, let7, KRAS, breast cancer, Hepatocellular carcinoma, colorectal cancer cells	[202,203,204,205,206,207,208]
c. Selective replication of virus in specific cells.
Promoter-based CRAd	Lung, prostate, ovarian, pancreatic cancer, adult T cell Leukemia/Lymphoma, glioma, meduloblastoma, sarcomas	[69,209,210,211,212,213,214,215,216,217,218,219,220,221,222]
CRAds based on Interaction of essential viral genes withTumor-specific proteins	colon, breast, non-small cell lung, head and neck, and pancreatic tumors, cervical carcinoma, glioblastoma, cancers with disturbed Rb pathway	[172,223,224,225,226,227,228]