Biodegradable nanoparticles (NPs) have been frequently used as
insulin transdermal delivery vehicles due to their grand bioavailability, better encapsulation, controlled release and less toxic properties. However, the skin's barrier properties prevent
insulin-loaded NP permeation at useful levels. Nowadays, microneedles have been spotlighted as novel transdermal delivery systems due to their advantages such as painlessness, efficient penetration and no hazardous residues. Herein, we introduce polymeric nanocarriers based on
carboxymethyl chitosan (CMCS) for
insulin delivery, combining with microneedle
therapy systems, which can rapidly deliver
insulin (INS) into the skin. The resulting CMCS-based nanocarriers are spherical nanoparticles with a mean size around 200 nm, which could generate supramolecular
micelles to effectively encapsulate
insulin (EE% = 83.78 ± 3.73%). A nanocrystalline microneedle array (6 × 6, 75/150 μm) was used to penetrate the stratum corneum (SC) for enhancing transdermal
insulin delivery, while minimizing the
pain sensation caused by
intravenous injection. Compared with the transdermal rate of passive diffusion [2.77 ± 0.64 μg (cm-2 h-1)], the transdermal rate of the
insulin-loaded NP combined with microneedle penetration shows a 4.2-fold increase [10.24 ± 1.06 μg (cm-2 h-1)] from permeation experiment in vitro. In vivo
hypoglycemic experiments demonstrate the potential of using nanocarrier combination with microneedle arrays for painless
insulin delivery through the skin in a clinical setting. Thus, the developed combination scheme of nanoparticles and microneedle arrays offers an effective, user-friendly, and low-toxicity option for diabetes patients requiring long-term and multiple treatments.