<p>Advanced drug delivery systems are superior alternatives for antihypertensive drugs with poor solubility and bioavailability. Cubosomes are lipid-based nanostructured particles with a cubic internal phase that function as drug carriers, improving solubility and permeability through skin. This study involves the development and evaluation of cilnidipine cubosomal nanogel patches (CLD CB NGP) for transdermal drug delivery. The CLD-loaded cubosomes were prepared by a top-down approach, optimized by a Box-Behnken design, and evaluated for particle size, encapsulation efficiency, zeta potential, and morphological structure. They were then developed into a polymeric nanogel patch using hydrophilic polymers. The transdermal patches were evaluated for surface morphology, swelling, bioadhesiveness, in vitro drug release, and ex vivo permeation through excised rat skin. The CLD cubosomes were polyangular nanoparticles (430&#xa0;nm), with high drug entrapment efficiency (80.8%) and good colloidal stability. The amorphization of the drugs within the drug carriers was confirmed by Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The CLD CB NGP showed a porous surface, good swelling properties, and excellent bioadhesiveness to gelatin films and rat skin. The cubosomes and CLD CB NGP showed significantly higher drug release and enhanced skin permeation (3.62-fold), with a higher steady-state flux (<i>J</i>_ss = 0.377&#xa0;mg/cm²/h), compared to control patches (<i>J</i>_ss = 0.104&#xa0;mg/cm²/h). The safety and biocompatibility were analyzed by skin irritancy studies and histology of rat skin, which revealed that the transdermal patches were non-irritant and safe for skin application. The study demonstrates an innovative drug delivery approach using cubosomes in transdermal patches for improved permeability, therapeutic efficacy, and sustained release.</p> Graphical Abstract <p></p>