. 2021 May 19;6(9):766–783. doi: 10.1038/s41578-021-00315-x

Table 2.

Anticancer functionalities of biomolecule-based nanostructures

Anticancer functions	Functional components	Aims and advantages	Refs
*Bypassing biological barriers*
Reduced immune recognition and RES clearance	Low-protein-adsorption peptides or polysaccharides; anti-phagocytosis peptides; blood cell membranes; albumin; DNA tetrahedron; ferritin	Prolonged circulation time and evasion of liver and spleen capture	^{34,90,175,177,233,234}
Enhanced extravasation	Albumin; leucocyte membranes; rod-like nanostructures	High intratumoural delivery efficiency; high exposure of functional elements to molecular targets; microenvironmental trigger	^44,146,175
Enhanced tumour tissue penetration	Albumin; stroma-targeted ligands; cell-penetrating peptides	Treatment of less accessible tumour cells deep within tumour tissue	^16,177
Delivery across the blood–brain barrier	Albumin; DNA tetrahedron; brain-targeted peptides	Treatment of brain tumours with intravenously delivered formulations	^27,175
Delivery across the air–blood barrier	Albumin	Facilitated pulmonary delivery of agents to treat lung cancer	¹⁷⁸
Delivery across the intestinal endothelium	Chitosan surface coating; endothelium-penetrating ligands	Treatment of intestinal gut tumours; orally administered chemotherapy	^49,61,65,235
*Tumour-targeted delivery*
Ligand-receptor recognition	Aptamers; albumin; peptides; folic acid; ferritin	Selective drug delivery to and accumulation in specific tissues, cells or subcellular organelles	^{18,58,67,88,90,91,99,150,177,179,233,234}
Protein corona manipulation	Adsorbed serum proteins		²⁷
*Stimuli responsiveness*
Stimuli-triggered decomposition of nanostructures	Protonable polysaccharides and peptides (pH); enzyme-cleavable peptides (tumour-specific enzymes); temperature-sensitive peptides (heat); disulfide bonds (GSH); irradiation-sensitive bonds (external light or radioactive irradiation); DNA nanoflower (H₂O₂); DNA nanohydrogel (pH); spherical nucleic acid (GSH); DNA origami (GSH); quantum dot DNA hydrogels (DNase); DNA coordination polymer (pH); albumin (H₂O₂); ferritin (pH); GroEL (ATP)	Rapid and complete drug release from otherwise stable nanostructures; selective drug release in desired location	^{16,59,63,93,157,216,234}
Stimuli-triggered (in situ) self-assembly (including gel formation) of nanostructures	Albumin; stimuli-responsive peptides	Delivery of nanostructures not suitable for administration in the assembled form owing to size, shape or mechanical properties	^148,150,179
Stimuli-triggered shape transformation of nanostructures	Peptide assembly; DNA origami (protein); DNA nanosuitcase (mRNA); DNA clamp (antibody); GroEL (ATP)	Rapid and complete drug release from otherwise stable nanostructures; selective drug release in desired location	^{3,95,96,99,150,216,217}
Stimuli-triggered activation and shedding of targeting, therapeutic or imaging functionality of nanostructures	Aptamer; ferritin; enzyme-cleavable peptides; breakable bonds	Minimization of non-specific nano–bio interactions; imaging signal detection during delivery; selective drug release in desired location	^55,88,191
Stimuli-triggered surface transformation (for example, charge reverse) of nanostructures	Protonable peptides and polysaccharides	Selective alteration of surface charge or functional groups at the tumour site to facilitate cell penetration, lysosome escape or other biological effects	⁵⁷
*Anticancer drug building blocks*
Targeting ligand	Antibodies; therapeutic peptides and aptamers	Low metabolic burden and minimal adverse effects	^{127,157,196,197,202}
Self-assembly material	Therapeutic peptides and aptamers, CpG DNA nanococoon, DNA–RNA nanocapsules, plant viral nanoparticles, protozoa protein, E2 subunit of pyruvate dehydrogenase	Low metabolic burden and minimal adverse effects	^{127,157,196,197,202}
*Combinatorial therapy*
Multidrug loading	Albumin; DNA origami; amphiphilic polysaccharides; amphiphilic peptides	Combined advantages of multiple drugs or therapeutic modalities; mechanism-based cooperation to improve tumour sensitivity to other treatment and to overcome resistance or to prevent recurrence	^{18,57,63,175,178}
Cooperation with immunotherapy	Immune cell-targeting ligands; DNA nanohydrogel; DNA–RNA nanocapsules; ferritin; hepatitis B core protein		^127,185,192
Cooperation with phototherapy or radiotherapy	DNA coordination polymer; albumin; nanostructures containing sensitizer or anti-angiogenetic drug		^67,93,176
*Theranostics*
Simultaneous imaging and treatment of tumour tissue	Nanostructures containing fluorophores; magnetic nanoparticles or other imaging agents	Simultaneous diagnosis of hidden tumours or small metastasis	^91,148
Real-time monitoring of drug release and activity	Separable fluorophore–quencher pairs; fluorescent molecules with stimuli-dependent emission properties	Monitoring of in vivo activity of nanostructures or tumoural response to delivered drug	¹⁴⁸

CpG, cytosine-phosphate–guanine; GSH, glutathione; RES, reticuloendothelial system.