Enhanced Dermal Delivery of Nanoparticulate Formulation of Cutibacterium acnes Using Sponge Spicules for Atopic Dermatitis Treatment

Youmei Jin,1,2 Chi Zhang,1,2 Mengnan Jia,1,2 Ming Chen1– 5 1Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen, 361102, People’s Republic of China; 2State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, Xiamen University, Xiamen, 361102, People’s Republic of China; 3Pingtan Research Institute of Xiamen University, Pingtan, 350400, People’s Republic of China; 4Shenzhen Research Institute of Xiamen University, Shenzhen, 518000, People’s Republic of China; 5State Key Laboratory of Vaccines for Infectious Diseases, Xiang’an Biomedicine Laboratory, Xiamen, 361102, People’s Republic of ChinaCorrespondence: Ming Chen, Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen, 361102, People’s Republic of China, Email [email protected]: The pathogenesis of atopic dermatitis (AD) is closely linked to both genetic and environmental factors, with patients often exhibiting a range of immunological abnormalities, including a pronounced Th2-type overreaction, which is a key feature of the disease.Purpose: Cutibacterium acnes has been shown to induce a robust Th1 immune response through intraperitoneal injections, potentially preventing the development of AD. In this study, a novel nanoparticulate formulation of Cutibacterium acnes (NFCA) was developed with the formulation optimization for the dermal delivery.Materials and Methods: Sponge Haliclona sp. spicules (SHS) were isolated from the explants of sponge Haliclona sp. with our proprietary method. The NFCA was prepared by high-speed grinding followed by film extrusion. The skin penetration of the model drugs in NFCA with SHS were visualized using confocal microscopy. The therapeutic effects of NFCA coupled with SHSs against AD in mice were assessed by using pathohistological examination and cytokine ELISA assay.Results: The NFCA particle size was 254.1± 39.4 nm, with a PDI of 0.29± 0.08 and a Zeta potential of − 7.9± 0.6 mV. SHS significantly enhanced total skin absorption of FD10K (39.6± 6.7%, p=0.00076) as well as deposition in the viable epidermis (3.2± 1.6%, p=0.08) and deep skin (dermis & receptor) (36.0± 5.9%, p=1.82E-5) compared to the control. In vitro cytotoxicity tests showed that NFCA had low toxicity to HaCaT cells (IC50=63.8 mg/mL). The study confirmed that NFCA can activate immune signaling pathways, promoting the high expression of IL-6 and IL-8 in keratinocytes, enhancing TNF-α and IL-1β expression in macrophages, and inducing Th1 and Th17-type immune responses. Furthermore, we demonstrated that the dermal delivery of NFCA using SHS in vivo significantly reduced epidermal thickness, serum IgE levels, and tissue IL-4 levels, thereby accelerating skin repair and mitigating Th2 polarization.Conclusion: SHS were employed to effectively deliver NFCA to the deeper skin layers to exert its immune functions. Moreover, the combination of SHS and NFCA can significantly cure mice with atopic dermatitis.Keywords: dermal drug delivery, sponge Haliclona sp. spicules, nanoparticulate formulation, Cutibacterium acnes, atopic dermatitis