Table 3.

Nanotherapeutic approaches to target non-cellular components of tumor microenvironment for overcoming cancer drug resistance.

Nanoparticles Platform	Targeted Component of TME	Drug/Therapeutic Agent/Surface Functionalization	Outcomes	Reference
Sorafenib (Sor) nanoparticles	Tumor hypoxia	Apoptosis inducer (CA IX-C4.16)	Synergistic therapeutic efficiency of CA IX-C4.16 and Sor combination	[147]
Terpolymer-Protein or protein-lipid nanoparticles	Tumor hypoxia	Manganese dioxide (MnO2)	Generation and delivery of different oxygen rates, 40% reduction in tumor growth in combination with radiotherapy	[148]
Carboxymethyl dextran nanoparticles	Tumor hypoxia	Doxorubicin and 2-nitroimidazole derivative	Selective accumulation of nanoparticles at hypoxic tumor tissues, high antitumor activity	[149]
Oxygen self-sufficient amphiphile (F-IR780-PEG) nanoparticles	Tumor hypoxia	Doxorubicin	Downregulation of P-glycoprotein expression, synergistic treatment by combination of chemotherapy and photodynamic therapy	[150]
CdTe quantum dots (QDs) conjugated with 2-deoxyglucose (DG)-polyethylene glycol (PEG), Lipoic acid, lysine, 9-poly-d-arginine	Tumor hypoxia	HIF-1α siRNA	Enhanced hypoxic tumor targeting, Excellent biocompatibility, perfect siRNA binding capability	[151]
Polyethylene glycol (PEG)-poly L-lysine (PLL)-poly lactic-co-glycolic acid (PLGA)-based nanoparticles	Tumor hypoxia	Transferrin (Tf) and daunorubicin (DNR)	Downregulation of HIF-1α expression, and induced apoptosis	[152]
Manganese ferrite nanoparticles	Tumor hypoxia	Mesoporous silica nanoparticles	Reduction in hypoxic environment with continuous O2-evolving property	[153]
Carboxymethyl dextran (CMD) and black hole quencher 3 (BHQ3) nanoparticles	Tumor hypoxia	Doxorubicin	Improved drug biodistribution, Enhanced toxicity under hypoxic conditions compared to normoxic conditions	[154]
Haemoglobin-based nanocarrier	Tumor hypoxia	Doxorubicin	Improved hypoxia induced chemoresistance reversal	[155]
Block copolymer nanoparticles	Tumor altered pH	Cisplatin, F3 peptide	Rapid tumor regression, avascular effect with significant vascular necrosis	[156]
Gold nanoparticles	Tumor altered pH	Doxorubicin	Elevated apoptosis, enhanced toxicity	[157]
Chitosan nanoparticles	Tumor altered pH	Mesoporous silica nanoparticles	Increased solubility and improved anticancer properties	[158]
Poly(L-histidine) (PHIS) and hyaluronic acid nanoparticles	Tumor altered pH	Doxorubicin, Anti-tumor immune regulator (R848)	Dual pH responsive nanoparticles, excellent tumor-targeting ability, inhibition of tumor growth	[159]
Multifunctional co block polymers-based nanosystems	Tumor altered pH	Doxorubicin, lectin	8-fold higher toxicity than free drug, 100% osteosarcoma cell death	[160]
Polyamidoamine (PAMAM) dendrimers	Tumor altered pH	Platinum-prodrug	pH-triggered size switching, improved drug penetration and therapeutic efficacy	[161]
Calcium carbonate aragonite nanocrystal	Tumor altered pH	Doxorubicin	Higher uptake of pH sensitive nanocrystals with great reduction of tumor growth	[162]
Micellar cationic lipid-assisted polymeric nanoparticles	Tumor altered pH	siRNA, Antibody of programmed cell death protein 1 (PD-1)	Neutralization of the tumor pH, significant inhibition of tumor growth	[163]
Magnetic nanoparticles	Alteration of metabolic pathways	Glucose	Enhanced internalization of glucose coated nanoparticles	[164]
Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES) nanoparticles	Alteration of metabolic pathways	Glutaminase inhibitor (CB-839), metformin	Effective inhibition of glutaminase, reduced tumor growth	[165]
Gold nanoparticles	Alteration of metabolic pathways	3-bromopyruvate (3-BP)	Enhanced ability to modulate cancer cell metabolism, mediating	[166]
Mesoporous silica nanoparticles	Tumor ECM modulation	Collagenase nanocapsules	Enhanced nanocarrier penetration, improved therapeutic efficiency	[167]
Liposome-based nanoparticles	Tumor ECM modulation	Collagenase, paclitaxel	Improved drug penetration, degradation of ECM correlated to reduction in metastasis	[168]