The emergence of MNs technology has changed the situation of traditional transdermal formulations limited by physicochemical properties of drugs (molecular weight, solubility, oil–water distribution coefficient, melting point, etc.), bringing more opportunities for the field of transdermal drug delivery (Glover et al., 2023, Vora et al., 2023, Zhang et al., 2023b). In 2020, MNs delivery technology ranked No. 1 on Scientific American's top 10 new technologies that are expected to change the world. Correspondingly, MNs are highly recognized in the scientific community and present great prospects for clinical applications. Recently, MNs, as commercially available products, have been widely used in cosmetics and medical devices (Ingrole et al., 2021, Zhang et al., 2023a). Nevertheless, there are currently no MNs available for clinical treatment, due to the challenges in safety, cost-effective fabrication, large-scale manufacturing, and so on (Aldawood et al., 2021).

Generally, the safety of MNs administration largely depends on the biocompatibility of the used materials (Jeong et al., 2017, Zhang et al., 2022b). A variety of materials such as stainless steel (Cahill et al., 2018), monocrystalline silicon (Howells et al., 2022), and polymers (Moniz et al., 2021, Singh et al., 2019) have been used to fabricate solid, coated, hollow, dissolving, or hydrogel MNs(Zhang et al., 2022a). Compared with MNs constructed of metal or silicon, which have poor flexibility that can easily be broken, and cause inflammation as embedded in the skin (Wu et al., 2023), MNs prepared with various polymers showed excellent biosecurity, low toxicity, and low cost (Singh et al., 2019). Polymers are usually employed in the fabrication of dissolving microneedles (DMNs) and HMNs (Al-Japairai et al., 2020). Especially, HMNs are the emerging and promising MNs mainly composed of swelling polymers (Wu et al., 2023). When HMNs are inserted into the skin, the needles absorb the interstitial fluid and then swell into a continuous 3D network micro-channel, thereby sustained releasing drugs. In addition, HMNs are unique in that they swelled rather than dissolving within the skin and can be completely removed from the skin after using, relieving the burden of polymers metabolism in the body (Hasnain et al., 2023, Liu et al., 2023). Overall, HMNs have higher safety, biocompatibility, and potential for clinical drug delivery.

PVA is one of the most used materials for HMNs, on account of its low toxicity and irritation to the human body, which has been approved by FDA (He et al., 2020, Oh et al., 2022, Yang et al., 2015). In addition, the characteristic of repeated hydroxyl groups makes it easy to form cross-linked polymers with good toughness, mechanical strength, and biocompatibility (He et al., 2020). Gelation of PVA HMNs can be obtained via two mechanisms, including chemical cross-linking and physical cross-linking (Pan et al., 2022). For the former, cross-linking agents, such as glutaraldehyde, citric acid, and other organic acid are generally required to produce covalent bonds and form the polymer network structure, resulting in lower biocompatibility and safety (Pan et al., 2022). For physical cross-linking, cross-linking junctions and crystalline domains based on repeated freeze–thaw process is the most classic method in PVA HMNs manufacturing (Yang et al., 2015). Specifically, MNs mold loaded with casting solution needs to be frozen at −20 °C to and then thawed at 4 °C (or room temperature), repeating this process several times. As a result, it is too cumbersome and time-consuming to achieve mass production. Besides, the good compatibility makes it often blended with other polymers to regulate the releasing and mechanical behaviors of HMNs, including chitosan (Hasnain et al., 2023), alginate (Zhou et al., 2022), and polyvinyl pyrrolidone (Xu et al., 2022b). In our previous study, pharmaceutical acrylic resin, Eudragit NM30D aqueous dispersion, was first used to mix with PVA for HMNs fabrication, based on hydrophobic interaction between two materials (Xing et al., 2023). However, aqueous dispersion properties of the Eudragit NM30D make it unsuitable for drug loading. Accordingly, developing industrializable and convenient approach for PVA HMNs fabricating is of great significance in promoting the application of HMNs in clinical therapies.

Like freeze-thawing process, anneal-swelling is another physical method to prepare cross-linked PVA hydrogel, which can form a large number of crystallites based on hydrogen bonding interaction within PVA chains (Ou et al., 2017). However, annealing treatment has not yet been applied to PVA HMNs, due to the fabrication process involving prolonged high-temperature condition, for example, drying at 80 °C for 3 h and annealing at 120 °C for 1 h (Ou et al., 2017). Infrared irradiation is a fast-heating method different from conventional high-temperature treatment, showing high efficiency, precise temperature control, low pollution, and high safety (Mohammadi et al., 2019). It has been widely used in medical, cosmetic, and diagnostic fields (Kang et al., 2020, Meng et al., 2023, Su et al., 2023). In this study, we first propose the use of infrared irradiation to prepare PVA HMNs based on anneal-swelling technology and develop an industrializable and convenient approach for efficient production of HMNs. According to the optimizations of fabrication process and formulation composition, HMNs with great swelling, mechanical, and biocompatible properties were acquired through infrared irradiation. Simultaneously, the cross-linking mechanism of HMNs has been analyzed by the in vitro characterization experiments. Based on our previous work, AZA and MAT, which displayed the effect of synergistic efficiency and toxicity reduction when combined use, were loaded into HMNs. We performed the stability, release kinetics, and in-vivo pharmacokinetics studies of drug-loaded HMNs. Furthermore, HMNs have been applied to tumor-bearing mice to achieve melanoma treatment.