Development of a Sensory Neuron-Integrated Skin Spheroid Model for the Evaluation of Neuropeptide-Based Topical Delivery Systems

Autor(es)

Martin, Bianca Aparecida ; Viegas, Juliana ; Dalmolin, Luciana Facco ; Santos, Emerson de Souza ; Vatanabe, Izabela Pereira ; Lisboa, Sabrina Francesca ; Lopez, Renata Fonseca Vianna ; Sarmento, Bruno

• Tipo de documento: Artigo Científico
• Fonte: ACS BIOMATERIALS SCIENCE & ENGINEERING; v. 11, n. 6, p. 20-pg., 2025-05-23.

Resumo

The skin is a complex organ composed of multiple layers and diverse cell types, including keratinocytes, fibroblasts, adipocytes, and sensory neurons, which maintain its structural and functional integrity together. Conventional in vitro and ex vivo models help investigate drug permeation and selected biological effects. However, they are limited in replicating neural interactions critical for assessing the efficacy of neuropeptide-based therapies. To address this limitation, a sensory neuron-integrated skin spheroid (SS) model was established, incorporating key skin cell types and providing a rapid, adaptable, and physiologically relevant platform for screening the biological activity of topical delivery systems targeting neuronal pathways. The model's responsiveness was demonstrated using acetyl hexapeptide-3 (HEX-3), a neuropeptide that inhibits acetylcholine release. HEX-3 was internalized by spheroid cells, with preferential accumulation around sensory neurons, confirming targeted cellular uptake. In parallel, ex vivo human skin studies confirmed that HEX-3 can traverse the stratum corneum and accumulate in deeper layers. Treatment with this film enhanced skin hydration, reduced scaling, and improved the structural organization of the stratum corneum after 48 h. Functional assays using the SS model showed that HEX-3 treatment suppressed acetylcholine release, upregulated the antioxidant enzyme SOD2, and stimulated type I collagen synthesis. In aged skin samples, the application of HEX-3 significantly increased collagen levels. This effect was mirrored in the spheroid model, which reached collagen levels comparable to those of aged human skin upon treatment. These findings establish the SS model as a robust platform for evaluating the biological activity of neuropeptide-based topical therapies, offering valuable insights for developing advanced strategies for skin rejuvenation and repair. (AU)

• Processo FAPESP: 22/03521-0 - Investigação de métodos físicos associados à sistemas de liberação de fármacos na resposta imune e antimicrobiana local
• Beneficiário: Renata Fonseca Vianna Lopez
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/50928-2 - INCT 2014: Nanotecnologia Farmacêutica: uma abordagem transdisciplinar
• Beneficiário: Maria Vitória Lopes Badra Bentley
• Modalidade de apoio: Auxílio à Pesquisa - Temático