Enhancing the Antitumor Efficacy of Nisin Through Advanced Nanosystems: A Systematic Review of In Vitro Studies

Background and Objectives: While nisin exhibits promising antitumor properties, its clinical utility is hindered by pharmacokinetic instability and rapid enzymatic degradation. This systematic review evaluates the critical role of advanced pharmaceutical formulations and targeted nanosystems in overcoming these limitations to enhance nisin's cytotoxic and pro-apoptotic efficacy in vitro. Methods: Following PRISMA guidelines, a comprehensive search was conducted across six electronic databases (PubMed, ScienceDirect, Scopus, Web of Science, SpringerLink, and DOAJ). In vitro studies comparing free nisin against polymeric, metallic, and cyclodextrin-based nanocarriers across diverse neoplastic lineages were included. Methodological quality was assessed using the SciRAP 2.1 tool, and a within-line comparative analysis was performed for MDA-MB-231 and HT-29 models. Results: Twelve studies met the inclusion criteria. A definitive technological inflection point was identified: nisin-loaded nanosystems reduced effective concentrations by up to 2706-fold relative to the free peptide in MDA-MB-231 cells, and 71-fold in A549 lung cancer cells. Mechanistically, nanosystems facilitated membrane pore formation, mitochondrial-mediated apoptosis via Bax/Bcl-2 modulation, caspase 3/7/9 activation, and p53 reactivation. Three previously underreported mechanistic dimensions were identified: TWIST1 downregulation and FZD7 binding in hepatocellular carcinoma, and downregulation of CEA, CEAM6, MMP2F, and MMP9F in colorectal cancer lines. Conclusions: The therapeutic viability of nisin in oncology is strictly dependent on pharmaceutical engineering. Future research must prioritize in vivo pharmacokinetic validation, experimental confirmation of novel mechanistic targets, and standardized nisin purity reporting to consolidate its clinical translation.