Acne vulgaris is a chronic inflammatory skin condition that markedly impacts well-being and life satisfaction. For many years, antibiotics have been a mainstay in the treatment of acne; however, excessive use of antibiotics has escalated a global issue of antimicrobial resistance. Oral spironolactone is currently used as an alternative treatment, acts as anti-androgen. There is growing interest in using topical spironolactone due to its systemic oral side effects. However, topical spironolactone faces challenges, such as poor solubility and limited permeation. To address these issues, a nanotechnology-based carrier, LeciPlexes, was developed to encapsulate spironolactone. To enhance spironolactone’s therapeutic efficacy, eugenol was incorporated, and the physicochemical characteristics of LeciPlexes and their potential application for topical delivery were assessed. The research began with a systematic review with meta-analysis conducted in accordance with PRISMA guidelines to assess the efficacy and safety of topical spironolactone for mild-to-moderate acne, followed by a second systematic review evaluating physicochemical characteristics of spironolactone nanocarriers and comparing them with conventional topical systems. The findings of the first systematic review indicated the safety and efficacy of topical spironolactone in reducing acne lesions and improving severity, while the second review stated the superiority of nanocarriers over conventional vehicles in enhancing its permeation and deposition. Moreover, LeciPlexes could offer potential benefits such as selective targeting of active sites, controlled drug release, enhanced permeation and deposition of drug into skin layers, and reduced systemic and topical side effects. LeciPlexes were prepared using two methods, a single-step method in which hot water was added to a warm blend of lipids containing spironolactone, cetyltrimethylammonium bromide (CTAB), and Transcutol-P under stirring, followed by a gradual addition of eugenol. The thin-film hydration method used rotary evaporation to form a lipid film from a mixture of CTAB, spironolactone and chloroform. This film was then hydrated with warmed water containing Transcutol-P under stirring, followed by the gradual addition of eugenol. Two similar formulations of eugenol- and spironolactone-loaded LeciPlexes were prepared using the single-step method: M3 (50 mg eugenol) and M0 (100 mg eugenol). Both reduced eugenol permeation amount and flux significantly; M3 increased spironolactone permeation flux two-fold compared to a control gel, whereas M0 achieved higher skin deposition. The thin-film hydration-based formulation (Mt) significantly improved spironolactone loading and doubled its permeation rate while reducing eugenol permeation rate by 1.5-fold. The in vitro drug release studies indicated that M3 and Mt exhibited sustained, controlled release of eugenol and spironolactone compared with the control gel, while M0 showed a faster release rate for both drugs. Storage at cold temperature (4 °C) improved the stability of LeciPlexe formulations. Overall, findings indicate that LeciPlexes are a promising carrier for the topical co-delivery of spironolactone and eugenol, providing improved drug loading and topical delivery targeting. Keywords: spironolactone, eugenol, LeciPlexes, acne vulgaris, topical delivery system, thin film hydration method, and permeation.