Table 1. Recent studies utilizing micro/nanotechnology in TB drugs since 2015.

	Aim	TB drug	Excipients	Dosage form	Method	Results
1 [64]	Design a pulmonary drug delivery of RIF	RIF	Soluplus	Micelles	A solvent-diffusion technique was employed to prepare the nanocarriers. Characterization: Size, morphology, in vitro release, stability, and cytotoxicity.	The solubility of RIF increased significantly when micelles (with a diameter of 107 nm) were formulated. The in vitro TB efficacy of the RIF-micelles was greater than the free drug at 24 h in vitro.
2 [65]	Encapsulation of many first-line TB drugs in one dosage form	RIF, NIH, PZA	Ethyl oleate (oil phase), Brij 96 (surfactant), butanol (Co- surfactant), and distilled water	Microe mulsion	A microemulsion consisting of an oil, surfactant, cosurfactant, and double-distilled water with constant surfactant-cosurfactant mass ratio was formulated. Characterization: Size, viscosity, loading efficiency, drug release, toxicity to Vero cells, and efficacy against several positive and negative gram bacteria.	The viscosity of the microemulsion did not change when the drugs were added and RIF (the most hydrophobic drug) was encapsulated within the core of oil droplet. INH was adsorbed to the aqueous side of the water-oil interface, and PZA (the most hydrophilic drug) was mainly dissolved in the aqueous bulk. The system was stable for 20 days at room temperature. The release profile followed a diffusional profile for INH and PZA, with analogous release for RIF. Toxicity was dependent on the concentrations but higher with ethyl oleate. The maximum antibacterial effect was observed for the RIF microemulsion and the RIF, PZA combination.
3 [66]	Compare the inhalation and oral routes of delivery of RIF microparticles	RIF	Dichloromethane	MP	MPs were prepared by the spray-drying method. Characterization: Size, aerodynamic diameter, in vitro release in simulated phagosomal and gastric fluids, in vivo deposition of the drugs.	Particles were produced with a median particle size of 3.6 ± 0.77 µm, a mass median aerodynamic diameter of 2.5 ± 0.061 µm, and emitted dose of 58.68 ± 0.84%. Full release of RIF was complete in 2 h in gastric fluid but only 53.35% was dissolved in phagosomal fluids. A high concentration of RIF was found in alveolar macrophages. No signs of hepatotoxicity were measured.
4 [62]	Prepare an inhaled delivery of RPN	RPN	PLGA	MP	MPs prepared by spray drying/oil-in- water (O/W) single emulsion solvent evaporation. Characterization: Morphology, size, thermal analysis, drug loading, in vitro dissolution, cytotoxicity, and macrophage uptake using THP-1 monocyte-derived macrophages.	Spherical MPs were prepared with a volume median size of 2 µm. 90% of the PLGA MPs were encapsulated by macrophages and the MPs were not toxic to the cells. The monomer molecular weight and composition did not influence the aerosol's performance and toxicity but increasing the lactide concentration enhanced uptake by macrophages.
5 [67]	The development of effective and safe nanotechnology-based methods	BDQ	Tween® 20, EtOH,Span® 85 (sorbitanetrioleate), Oleic acid, and chitosan	Nano capsule	NPs were prepared by blending lipid and aqueous phases using an ultrasonic process to provide stable nanodroplets.Characterization: Encapsulation efficiency, drug loading, in vitro efficacy against Mycobacterium tuberculosis, and cytotoxicity on animal cells.	Nanocapsules successfully encapsulated the drug. The antibacterial efficacy was increased significantly, with rapid interaction with TB bacteria. No cytotoxicity was shown towards animal cells for any of the therapeutic concentrations of the drug.
6 [68]	Achieve synergistic treatment using nanoparticles	INH, MX	Chloroacetyl chloride (CAC) & succinyl chloride (SCL) to modify the drugs and PLGA for encapsulation	NP	NPs were prepared by a single emulsion reaction after linking the drugs together through nucleophilic substitution reaction. Characterization: Compatibility, particle size, size distribution, Zeta potential, drug entrapment efficiency, drug release, and accelerated stability studies.	An enhanced effect of the two drugs was achieved, when they were delivered inside the NPs and the NP formulation achieved better antibacterial activity than the free mixture of the drugs.
7 [69]	Deliver ETH and its booster effectively to the lung	ETH, BDM 41906	Poly (lactic acid) (PLA) and PLGA	NP	Different forms of nanoencapsulation were prepared. Nanoprecipitation of ETH with PLGA and PLA was performed using DMSO. A nano- emulsion of ETH was prepared using MeOH and dichloromethane (DCM). ETH and its booster were encapsulated without using solvents. Characterization: Shape, size, zeta potential, drug loading and their effect on mouse macrophage RAW 264.7 infected by the M. tuberculosis H37Rv strain.	300 nm NPs were prepared with the solvent, with a loading efficiency of 77% Without the use of the solvent, 10 nm NPs were produced. The NPs were delivered to the lungs using a Microsprayer® which gave a decrease by 3-log of pulmonary mycobacterial count after 6 administrations, suggesting that a combination of ETH and its booster increased the potency of the individual drugs.
8 [70]	Enhance the bioavailability of the drug	RIF	Compritol 888 ATO,Span® 80 and stearylamine	NP	NPs were prepared by an O/W microemulsion method followed by a high-pressure homogenization technique.Characterization: Size, zeta potential, entrapment efficiency, drug loading, morphology, in vitro release, and stability study for 6 months at 8 °C, 30 ± 2°C/65 ± 5% RH, and 40 ± 2°C/75 ± 5% RH.	NPs with a diameter of 456 ± 11 nm and encapsulation efficiency of 84.12 ± 2.78%, were stable in different simulated gastrointestinal tract media. The drug was released in biphasic profile with 90% of the drug was released within 120 min and the best fitting model was Weibull. An accelerated stability test did not alter the physical stability of the NPs.
9 [71]	Design a controlled release of IV delivery	LZ	PLGA 752 H	NP	Nanoparticles were prepared by a solvent evaporation technique using high speed homogenization. Characterization: Size, zeta potential, encapsulation efficiency, antibacterial efficacy, in vitro dissolution test using lung simulated fluid, and in vitro deposition in the lung using an Anderson Cascade Impactor.	NPs were prepared with a size <300 nm with a correlation between the size and homogenization speed and time. The NPs had an encapsulation efficiency up to 85.33%. These NPs showed a sustained release up to 2 h. The deposition studies showed the particles have potential to reach the alveolar unit in vivo.
10 [72]	Improve TB treatment by designing RIF nanoparticles	RIF	PrecirolR ATO 5polysorbate 60 and miglyol-812	NP	High shear homogenization and ultrasonication techniques were used to prepare the particles and they were coated with mannose. Characterization: Size, zeta potential, drug loading, morphology, toxicity on Bone marrow-derived macrophages, drug efficacy on the Mycobacterium avium strain 2447.	Spherical NPs with a mean size of 315 nm, and encapsulation efficiency of 95% were prepared. Efficient uptake of mannosylated NPs by bone marrow-derived macrophages was observed and improved antibacterial efficacy was observed for RIF mannosylated nanoparticles compared with the free RIF.
11 [73]	Design a pulmonary delivery of ETM to the lungs	ETM	Compritol and Tween 80	NP	Hot homogenization and ultrasonication methods were used to prepare the NPs and the dry powder inhaler was prepared by spray drying. Characterization: Flowability, deposition, encapsulation, size, and toxicity on a A549 cell line.	An encapsulation efficiency of 98% was achieved with a NP size of< 100 nm. Release of EMT from the nanoparticles was less than the free drug with 34% after 8 h. No significant toxicity was observed for any of the NP formulations compared with the free drugs.
12 [74]	Study the effect of human serum albumin as a carrier to deliver TB drug	BTZ	Albumin	NP	NPs were prepared by a modified desolvation method. Characterization: Size, polydispersity index, zeta potential, in vitro release and antibacterial effect using murine bone marrow-derived macrophages (mouse strain C57BL/J) were studied and the in vivo efficacy was tested in mice.	Incubation with Albumin enhanced the solubility of BTZ. The encapsulation efficiency was 37–60% with more than 50% of the drug released within 4 h. The antibacterial effect of BTZ was enhanced by formulation of the drug inside the NPs.
13 [75]	Validate the high intracellular uptake of nanoparticles	RIF, CUR	Polyethylene sebacate and Tween 80	NP	NPs were prepared by a nanoprecipitation method. Characterization: Entrapment efficiency, particle size, zeta potential, morphology, in vitro release, cell viability, and TB efficacy.	NPs with a diameter of 434 nm and zeta potential of −26.89 mV were obtained. The NPs were not toxic and macrophage uptake was enhanced by 1.5×. Importantly, dual-loaded TB drugs could be a promising approach to TB treatment.
14 [76]	Explore the bactericidal effects of selenium nanoparticles	INH,	Selenium and chitosan	NPs	A versatile method was used to prepare the NPs.	The NPs preferentially entered macrophages and accumulated in lysosomes.
15 [77]	Decrease the dose of MOX and AMI	MOX, AMI	PLGA, Alginate	NPs	Two formulations were used: 1- alginate was utilized as a coating polymer of the PLGA NPs. 2- alginate was entrapped in the internal phase to increase the drug encapsulation.	The 1-alginate NPs had a size of 640 nm and negative zeta potential and the 2-alginate particles had a size of 420 nm and positive zeta potential. Both formulations showed a similar drug release profile and were internalized by macrophages. Importantly, dual loading of TB drugs showed an enhanced antibacterial effect compared with single anti-TB drug.
16 [78]	Design of effective and safe drug delivery system	RIF	MPEO-b-PCL	NP	NPs were prepared by a nanoprecipitation method.Characterization: Size, Zeta potential, morphology, cytotoxicity, and efficacy on BEAS-2B, J774A.1, and MH-S cell lines.	Formulating RIF within a biodegradable copolymer enhanced the pharmacokinetics and pharmacodynamics of the drug. It was well tolerated, and the antibacterial effects was improved compared with the free drug.
17 [79]	Find better- sustained treatment for TB	RIF, INH	Glyceryl distearate (GDS), precirol ATO- 5, Soybean phospholipids, Tween- 80, Poloxamer-188 and dimethyl sulphoxide (DMSO)	Nanostr uctured carriers and solid nanopart icles	NPs were prepared by mixing in heated aqueous and lipid phases to form emulsion following by homogenization with cold aqueous phase. squalene was added to prepare nanostructured carriers. Characterization: Size, zeta potential, encapsulation efficiency, morphology, in vitro drug release, toxicity to THP-1, and	Spherical NPs with a diameter of ∼ 150 nm were prepared and showed a sustained release pattern for INH and RIF over 2 and 7 days, respectively. The NPs were localized in the endosomes and lysosomes. The pharmacokinetic profile of these drugs formulated inside the nanostructured lipid carriers was improved compared with the solid NPs.
					pharmacokinetics in rats when INH or RIF solution was administered orally
18 [80]	Prepared curdlan nanoparticles loaded with TB drugs	RIF, LVX	Curdlan	NP	NPs were prepared by a nanoprecipitation method.Characterization: Drug loading, in vitro drug release, minimum inhibition concentration for M. smegmatis, and uptake by RAW 264.7 macrophages.	NPs with a median size of 600 nm sacrificed 95% of bacteria within 4 h, were non-toxic for cells, their uptake by macrophages increased significantly and the drugs were released completely within 70 h.
19 [81]	Using Chitosan to design a mucoadhesive drug delivery to the lungs	RIF	Cetyl palmitate, Tween® 80, and chitosan®	NP	NPs were prepared by a hot ultrasonication method. Characterization: Size, morphology, zeta potential, encapsulation efficiency, stability, in vitro release, toxicity on A549 cells.	NPs with a diameter of 245–344 nm and zeta potential of −30 mV were coated with chitosan. The encapsulation of the drug efficiency was 90%. Results showed higher mucoadhesive and permeability to alveolar epithelial cells compared with the uncoated nanoparticles containing the drug.
20 [82]	Design a selective NP drug delivery system.	RFB	Precirol® ATO 5, miglyol-812, stearyl amine, D- (+)- Mannose	NPs	NPs were prepared by high-shear homogenization and ultrasonication. Characterization: Size, zeta potential, morphology, entrapment efficiency, cytotoxicity on human airway epithelial cell line Calu-3, human bronchial epithelial cell line A529, and murine macrophage RAW 264.7 cells and drug release kinetics.	Spherical NPs with a size 175–213 nm were coated by mannose, had an encapsulation efficiency of 80% and were stable for 6 months in room temperature. The drug release was faster in acidic pH with a full release of the drug within 25 h. The system showed the possibility of increasing the dose above 100 µg/ml and less than 1000 µg/ml before reaching the inhibitory concentration IC50 which was 238.9, 185.7, and 108.7 μg ml−1 for Calu-3, A549s, and RAW macrophages.
21 [83]	Enhance the efficacy and the uptake of RIF	RIF	Stearic and oleic acid as lipid phase, Tween 80, and Phospholipid 80H as surfactants. N, N- dimethylformamide(DMF) and methanol as solvent	NPs	Tuftsin-modified peptide (pTUF-OA) was synthesized using a solid-phase approach and NPs were prepared by a microemulsion technique.Characterization: Size, zeta potential, morphology, stability, encapsulation efficiency, in vitro drug release, uptake by Murine macrophages using a J774 A.1 cell line, and cytotoxicity.	The synthesis of pTUF-OA was successful, and RIF was incorporated in the nanocarriers leading to a nontoxic controlled- release therapy. The NPs with the peptide showed increased uptake by macrophages compared with the NPs without the peptide but both showed a significant improvement in antitubercular effect compared with free RIF.

The abbreviations of drugs listed in the table are Rifampicin: RIF; Capuramycin: CM; Isoniazid: INH; Pyrazinamide: PZA; Streptomycin: SM; Moxifloxacin: MX; Ethionamide: ETH; Linezolid: LZ; Ethambutol: ETM; Thioacetazone: THI; Rifabutin: RFB; Rifapentine: RPN; Benzothiazinone: BTZ; Curcumin: CUR; Moxifloxacin: MOX; Amikacin: AMI; Levofloxacin: LVX; Bedaquiline: BDQ.