•LAB have been successfully used in the last years as safe mucosal delivery vectors.•L. lactis is considered as the model LAB and an excellent vector of medical proteins.•We report on the development of a Stress-Inducible Controlled Expression (SICE) system.•We validated SICE system in a model of therapy against IBD.•We validated SICE system in a model of mucosal vaccination against HPV-16. In recent years, recombinant lactic acid bacteria (LAB) have been successfully used as safe mucosal delivery vectors. Herein, we report on the development of a Stress-Inducible Controlled Expression (SICE) system in L. lactis for the production and delivery of proteins of health interest (both therapeutic and vaccine related) at mucosal surfaces. This system is episomal in nature and is composed of a vector carrying an expression cassette under the transcriptional control of a stress-inducible promoter. The functionality of the SICE system was validated in vivo using two different routes of administration: oral and intranasal, and in two different murine models of human pathologies: (i) a model of therapy against inflammatory bowel diseases (IBD) and (ii) a model of vaccination against human papillomavirus type-16 (HPV-16).