Generally, low bioavailability and small absorption of poorly soluble drugs represent major problems in the pharmaceutical drug development (Savjani et al., 2012). Numerous efforts have been made to increase the solubility and biodistribution of poorly soluble drugs (Nagarwal et al., 2011), among which nanocrystal technology plays an important role in addressing the problems associated with low solubility of drugs. Nanocrystals are carrier-free drug particles within nanometer size range, and have increased dissolution rate due to increased surface area, thus possessing enhanced bioavailability (Srivalli and Mishra, 2015). Moreover, owing to the structure of non-polymer covering, nanocrystals have high drug loading capability (as high as 100%), which makes them extremely attractive for treatments of the diseases that usually require high drug doses. A further characteristic of nanocrystals is that they can achieve sustained release of the drug for an extended period at the administration site due to the slow dissolution in the aqueous environment (Permana et al., 2020).

Lipid-based nanoparticles are most typically spherical vesicles with single or multi-lipid bilayers that encapsulate aqueous droplets, and the lipid-based nanoparticles mainly include: liposomes, nanoemulsions, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) (Vitorino et al., 2014). Due to the lipophicity of the nanoparticles, they are beneficial to increase solubility of poorly water-soluble drugs, thereby enhancing bioavailability. Besides, lipid layers of nanoparticles can fuse with stratum corneum lipids to further improve the drug transport through the skin (Kuntsche et al., 2008). As one kind of the most prevalent lipid-based nanocarriers, liposomes are usually made of phospholipids that can form unilamellar and multilamellar vesicular structures, which makes liposomes suitable to carry and deliver hydrophilic, hydrophobic or lipophilic drugs (Mitchell et al., 2021).

Polymeric nanoparticles used for drug delivery offer many special advantages over other kinds of nanoparticles, including increased target ability after surface modification, improved biocompatibility, reduced cytotoxicity and prolonged drug release duration (Begines and Ortiz, 2020). A variety of natural or synthetic polymers have been used in polymeric nanoparticle formulations, such as poly (D, l-lactide-co-glycolide) (PLGA), poly (lactic acid) (PLA), polyethylene glycol (PEG), polyacrylates, chitosan, alginate, gelatin and albumin (De Jong and Borm, 2008). Among the above polymers, PLGA is the most frequently used hydrophobic polymer because of its excellent biocompatibility and slow biodegradation rate, which makes it appealing for the development of controlled release formulations (Naves et al., 2017), and PEG is the most commonly used hydrophilic polymer with non-immunogenic, biocompatible and flexible nature, which makes it suitable for the delivery of hydrophilic drugs or bioactive molecules that usually require mild condition during encapsulation process (Jeyhani et al., 2019).

Inorganic nanoparticles are non-toxic, hydrophilic, biocompatible and highly stable, which makes them ideal for drug delivery. Inorganic nanoparticles for drug delivery mainly include mesoporous silica nanoparticles (MSNs), superparamagnetic iron oxides (SPIONs), quantum dots and metallic nanoparticles. MSNs have been widely used as controlled release carriers for drugs due to their large specific surface area, regular pore structure, adjustable pore size and good biocompatibility. Meanwhile, their unique mesoporous structure can prevent drugs from enzyme degradation or early release. In addition, the porous surface is covered with a large number of silica hydroxyl groups, which enables mesoporous silica nanoparticles to be functionalized by post-modification with a variety of polymers or specific drugs, forming intelligent drug control systems (Choi et al., 2021). SPIONs are kind of magnetic nanoparticles that can be guided by the direction of external magnetic field. Besides, they can also be used as contrast agents for magnetic resonance imaging (MRI) for diagnosis of diseases (Zhu et al., 2017). Quantum dots are semiconductor nanomaterials with diameters between 2 and 100 nm, usually prepared from III–V or group II–VI elements. Quantum dot excitation light has wide band range, narrow emission spectrum width, high fluorescence intensity, good stability, long life and certain antibacterial activity (Ren et al., 2020), which makes it have a good application prospect in wound healing (Salleh and Fauzi, 2021), drug transport (Fakhri et al., 2017), fluorescent biosensors (Hu et al., 2021) and disease diagnosis (Mansuriya and Altintas, 2021). In recent years, metallic nanoparticles have attracted growing interest in drug delivery, and the modification and functionalization of metallic nanoparticles with specific functional groups allow them to bind to antibodies, drugs and other ligands, making metallic nanoparticles promising in biomedical applications (Patra et al., 2018).

The most typical strategy of MN-mediated transdermal delivery of nanoparticles is the topical application of a formulation containing nanoparticles after MNs pretreatment, which created microscopic puncture holes in the skin allowing nanoparticles to diffuse through the skin (Figure 2) (Eneko et al., 2016). Zhang et al. used confocal laser scanning microscopy to visualize the distribution of fluorescent PLGA nanoparticles in the skin through the microchannels produced by solid MNs application, and they observed a great number of nanoparticles could travel and deposit in Epidermis located below the stratum corneum, demonstrating the enhanced transdermal delivery of nanoparticles facilitated by solid MNs pretreatment (Zhang et al., 2010). This strategy has the advantage of enhancing skin permeation of nanoparticles, while it still suffers from limited drug amount that can be transported through the skin (Alimardani et al., 2021).

Hollow MNs are also beneficial for transdermal delivery of nanoparticles, which allows for continuous delivery of liquid nanoparticle formulations, like nanoparticle suspensions, into the skin through the inserted hollow needles. Such kind of MNs is possibly capable of precisely delivering larger amounts of nanoparticles with spatial and temporal resolution compared to solid MNs (Roxhed et al., 2008). For example, Mir et al. developed a liquid injection system (AdminPen®) by combining bacterial enzyme-responsive nanoparticles with hollow MNs. In vivo skin insertion and dermatokinetic studies suggested that the system delivered about 8.5 times higher concentrations of the drug, carvacrol (CAR), in the form of NPs as compared with topically applied hydrogel containing pure CAR, indicating a great potential of increasing transdermal delivery of nanoparticles by hollow MNs (Mir et al., 2020). In spite of the capability of enabling transdermal delivery of precise and increased nanoparticles facilitated by hollow MNs, such strategy is compromised by the use of complicated setups.

Coated MNs that contain a nanoparticle formulation at the surface can completely dissolve the coating and subsequently deliver the nanoparticles at the administration site upon skin insertion. Coated MNs are generally made of solid MNs and surface coatings that can be prepared by various methods such as dip coating (Ma and Gill, 2014), spray coating (Ning et al., 2020) and other sophisticated methods (Tort and Mutlu Agardan, 2020). For example, DeMuth et al. designed PLGA MNs coated with cationic poly (β-amino ester) (PBAE) and negatively charged interbilayer-cross-linked multilamellar lipid vesicles (ICMVs) for delivery of protein antigen and the antigen adjuvant (DeMuth et al., 2012). This coating of PBAE and ICMV rapidly transferred from the MNs to the skin after MNs insertion, leading to an efficient delivery of antigens to antigen-presenting cells and inducing a robust immune response (Figure 3) (DeMuth et al., 2012). Although this method is very straightforward, but it still suffers from limited amount of nanoparticles that can be delivered into the skin via coated MNs (Kim et al., 2012).

The grim situation of poorly soluble drugs in the topical application has encouraged the combination of drug nanocrystals or drug-loaded nanoparticles with dissolvable MNs (Figure 4) (Lee et al., 2014). Unlike coated MNs, dissolvable MNs can get dissolution of the whole MNs and then release the encapsulated nanocrystals or nanoparticles at the administration site under skin, which makes dissolvable MNs be able to deliver more nanoparticles compared with coated MNs. For example, methotrexate sodium salt (MTX Na), a drug for psoriasis treatment, is poorly water soluble and hard to be used topically. Such drug could be made into nanocrystals and incorporated into dissolvable MNs. After skin insertion, the MTX nanocrystal-carrying MNs exhibited desired drug delivery efficiency, showing approximately 322-fold higher accumulation in the skin 24 h after administration than free MTX. In vivo studies in rats revealed that 72 h after administration, there was still about 12.5% of the MTX nanocrystals deposited in the skin, suggesting a localized and sustained drug delivery facilitated by the strategy of dissolvable MNs and nanotechnology (Tekko et al., 2020).

Electric-field related methods have been used as auxiliary means for better drug transport (Niamlang and Sirivat, 2009). Transdermal iontophoresis is a physically noninvasive method that involves applying a low electrical potential gradient across the skin to facilitate the passage of charged or polar substances through the skin (Katikaneni et al., 2009). However, the use of iontophoresis alone still has limited improvement and do not significantly promote drug penetration from stratum corneum to deeper layers (e.g., Epidermis and dermis), especially for those biological macromolecules such as proteins or DNA. The strategy of combining iontophoresis with MNs can significantly improve the transdermal delivery efficiency as well as broaden the diversity of drugs ranging from small chemicals to large molecules or drug-loaded nanoparticles (Katikaneni et al., 2009; Lanke et al., 2009; Vemulapalli et al., 2012; Gaware et al., 2019). For example, Chen et al. investigated the transdermal delivery of insulin-loaded nanovesicles driven by iontophoresis through microchannels created by solid MNs (Chen et al., 2009). Facilitated by MNs puncture, in vivo permeation study exhibited 86.1–166.7 times higher drug permeability than that without MNs pretreatment. Further, under the influence of a forward current, the positive charged nanovesicles accelerated the movement towards deeper site of skin through the microchannels created by MNs and showed 3.4–7.1 times higher than nanovesicles with MNs pretreatment alone, suggesting the greatly improved delivery efficiency of nanoparticles when using MNs and iontophoresis together. Although this method possesses significantly enhanced efficiency for transdermal delivery of drug-carrying nanoparticles, it is only restricted to polar substance and has limited effect for neutral nanoparticles compared with the approach of MNs pretreatment alone.