Drug delivery systems (DDSs) release drugs through specific control devices and certain doses to achieve the purpose of enhancing the immunity of the body or treating diseases [106,107]. It is difficult to advance medicine without the use of medications. While drug activity is crucial, the method of administration is more so. Pharmacokinetics (PK), duration of action, metabolism and toxicity are the key elements that influence drug delivery [108]. NNHs inherit the excellent biocompatibility and high specific surface area of electrospun fibers but also the function of NPs, which can load different drugs into NNHs for a precise controlled release [109,110]. The advantages of NPs are their high specific surface area, superior bioavailability and functionalization. Similarly, in practical drug delivery applications, nanofibers can be electrospun with biocompatible polymers, resulting in minimal harmful effects on humans [111]. Tuğcu-Demiröz and co-workers employ ionic gelation to load benzydamine onto chitosan NPs. Composite NPs were embedded in NFs and hydrogels, respectively. On the one hand, NFs have a large specific surface area. The medicine, on the other hand, diffuses across a short distance in the fiber. Benzydamine released 53.03% in the composite fiber system after 24 h. Because of the strong polymer matrix, the hydrogel system only released 15.09% of benzydamine. This is insufficient for the required drug concentration for vaginal infections [112]. In the process of release, benzydamine enters the nanofiber after the initial release of chitosan nanoparticles, and the secondary release can achieve a slow release and prolong the action time.

For the mechanism of release of NNHs-loaded drugs: (1) one drug in two phases: the drug is loaded on nanoparticles that need to cross the barrier between nanoparticles and nanofibers during the release to achieve the effect of slow release. (2) Dual drug biphasic: two drugs are loaded in separate materials with different properties to achieve the required effect by different types of release mechanisms.

Recently, with the abuse of antibiotics, different types of drug-resistant bacteria emerged [39,132,133,134], and the combination of different types of materials based on NNHs can also generate excellent antibacterial ability against drug-resistant bacteria. The preparation of NNHs by loading the bactericidal nanoparticles in the precursor solution begins with the mixed uniform solution, which is prepared into fibers by ESP. Mainstream bactericidal nanoparticles mainly include metal (AuNPs [135,136], AgNPs [137,138]) and metal oxides (ZnO [139], CuO [140] and TiO₂ [141]), etc. The accumulation of AgNPs in mitochondria leads to mitochondrial dysfunction. Additionally, AgNPs disrupt the DNA structure, resulting in non-replication and effectively suppressing bacterial multiplication. These two fundamental factors lead AgNPs to possess potent bactericidal potential [142]. Li et al. manufactured PCL nanofibers loaded with AgNPs and cisplatin (DDP), which can be used to prevent airway inflammation and resist granulation tissue proliferation. In comparison with the control group, the PCL-DDP-AgNPs scaffold showed no adhesion to rabbit peritracheal tissues, while the coated plate had a superior antibacterial effect [137]. Yang and co-workers prepared Janus nanofibers PVP-CIP/EC-AgNPs by loading AgNPs on the EC side through bide-by-side electrospinning. The Janus fibers from the disc-diffusion experiment showed a larger circle of inhibition against S. aureus and E. coli than fibers loaded with a single antimicrobial agent, which may be due to the simultaneous action of AgNPs and CIP, steadily increasing the antimicrobial capacity [132]. AgNPs are easily aggregated in polymer fibers, which affects the mechanical properties of the fibers and significantly compromises the antibacterial effect. Bakhsheshi-Rad et al. doped GO/AgNPs into PLLA fibers. They deposited composite fibers onto a bio-implant Mg alloy. SEM images of composite fibers co-cultured with bacteria revealed considerable bacterial cell membrane disruption. When compared to PLLA nanofibers, GO/AgNPs/PLLA efficiently inhibits bacterial proliferation [133]. This strategy provides new ideas for surface modification of metallic biomaterials, but high concentrations of AgNPs possess a degree of toxicity to normal cells. There is no presence of Ag elements in the organism. For example, if they are mostly deposited inside the liver, they will cause irreversible damage to the organism. Therefore, how to effectively and precisely control the amount of AgNPs released deserves researchers’ deep thinking [143]. There is a similar situation for AuNPs. Ibrahim et al. employed carboxymethyl chitosan (CMCS) as a green reducing agent for AuNPs. AuNPs were encased in PVA nanofibers. This technique reduces the cytotoxicity of AuNPs generated by the chemical reductant method while efficiently preventing bacterial growth. It signifies that safety has been improved further [135].

Simulating the structure and composition of the extracellular matrix (ECM) is a method to provide suitable conditions for cell adhesion, differentiation and proliferation. Researchers have found that electrospun fibers are identical in properties to natural tissues through the intersection of biological, medical and nano-engineering technologies [149,150] while offering high porosity. Electrospinning (ES) is considered one of the most eligible technologies for tissue engineering, providing scaffolds for tissues to mimic ECM composition and deliver Biofactors, thus promoting the growth of new tissues [151].

Lu and colleagues used SiNPs deposited on the surface of PLLA electrospun fibers, which effectively enhanced the mechanical properties and hydrophilic ability of the composite membrane, leading to better biocompatibility and promoting cell adhesion and proliferation [152]. Orthopedic clinical challenges are surgical risks of bone loss aptamers and pathogenic infections. Placing autografts or an Allograft is the best clinical option to combat bone loss but with immune rejection problems and infection risks [153]. Following the development of NNHs, electrospun fiber tissue engineering scaffolds can be fabricated from nanofibers and several nanoparticle hybrids, which mainly include: inorganic nanoparticles (nanohydroxyapatite (nHA) [154], calcium phosphate (CaPs) [155], Molybdenum Disulfid (MoS₂) [156], Cerium dioxide (CeO₂) [63] and Magnesium oxide (MgO) [157]) and metal nanoparticles (gold nanoparticles (GNPs) [158]), etc.

Nanohydroxyapatite (nHA) enhances the osseointegration and osteoconductive properties of hard tissues by embedding itself in the collagen matrix of hard tissues. Song and co-workers spun NELL-1 functionalized chitosan nanoparticles (NNPs) and nHA in PCL fibers. By incorporating the NPs into PCL electrospun fibers, the authors clearly increased the fiber diameter and demonstrated that nHA and NNPs enhanced cell adhesion sites. nHA presence compared to unmodified nanofibers MC3T3-E1 cell proliferation and differentiation were enhanced [159]. Liu and colleagues prepared hydrogel fibrous scaffolds containing gelatin-methacryloyl (GelMA) and calcium phosphate nano-particles (CaPs). After 14 days of incubation in SBF, significant mineralized nodules developed on the surface of CaPs@GelMA-F. Faster Ca²⁺ deposition in the early stage can significantly boost the development of calcified nodules later on. Moreover, bone defects are accompanied by rupture of blood vessels. CaPs@GelMA-F cells were co-cultured with HUVECs cells, resulting in pictures of dense vascular network topology. CaPs@GelMA-F is also very effective in promoting angiogenesis [160].

Because of its unique physicochemical properties, where S is an important component of many amino acids in living organisms, MoS₂ is also an essential trace element in the human body [141]. Researchers found that doping MoS₂, a two-dimensional material, with nanofibers can effectively promote cell proliferation and maintain cell viability of BMSCs, and at the same time, the higher the MoS₂ content, the stronger the osteogenic ability [161,162]. Furthermore, Ma et al. found that the NIR photothermal properties possessed by MoS₂ can respond quickly, reaching the optimal temperature required for osteogenesis (40.5 ± 0.5 °C) in 30 s with 808 nm NIR irradiation. The BV/TV capability under NIR irradiation reached 41.41 ± 0.52% [156].

In addition to the various applications in osteogenic tissues, NNHs also have a positive role for other tissue engineering formation. Neural tissue engineering (NTE) is an emerging field. Material preparation requires excellent biocompatibility, certain mechanical properties and good permeability to oxygen and nutrients, etc. [163]. Chen and co-workers demonstrated the combination of melatonin MLT and Fe₃O₄-MNP with PCL to prepare an outer-middle-internal triple-layer structural scaffold of PCL, Fe₃O₄-MNPs/PC and MLT/PCL, with MLT effectively reducing oxidative loss. The results revealed that the scaffold had a medullary axon diameter (3.30 μm) similar to the autograft group, which significantly promoted neuronal axon growth[164]. Myocardial infarction is one of the more common diseases in humans. Myocardial cells are gradually replaced by scar tissue after necrosis, leading to heart failure and arrhythmias caused by changes in electrophysiological properties, so it is most important for cardiac tissue engineering to have excellent elasticity, high electrical conductivity and promote the growth of myocardial cells [165]. Zhao et al. employed the ES process to create carbon nanotube/silk protein (CNT/silk) scaffolds. The majority of carbon nanotubes are contained within the fibers and dispersed along the fiber development direction. Compared to monospun silk protein, the elongation at the break of the composite fiber is up to 200% or more, and the tensile strength reaches 5.0 Mpa. The CNT/silk stent’s excellent electrical conductivity implies that it is efficient in avoiding arrhythmia[166].

The human immune system’s first line of defense is the skin. Skin injury is common in everyday life. Wound dressings to meet the demands of skin tissue engineering are scarce. A great wound dressing must not only support ECM regeneration but also protect the skin from exogenous microorganisms [168]. NNHs fulfill the need for skin tissue engineering owing to their versatility. Janus nanofibers were loaded with AgNPS and RCSPs to impart antibacterial ability and bioactivity to electrospun fibers. In the present work, interestingly, Janus nanofibers can be obtained based on the uniaxial electrostatic spinning process through the presence of phase separation of PCL and PVP in a solution. AgNPS in the free state is very susceptible to phagocytosis by normal cells due to its fine particles and exists a certain degree of cytotoxicity, and RCSPs-Ag nanofibers in this study had only 78.86% viability on NIH 3T3 cells [169]. The team designed a sandwich wound dressing with AgNPs loaded with an intermediate layer of nanofibers to both impede the invasion of exogenous microorganisms and avoid cytotoxicity [167].