Purpose: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. Experimental Design: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. Results: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMBoverexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. Conclusions: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

Therapeutic proteins and peptides are very attractive from the pharmaceutical point of view due to their high potency and selectivity. Nonetheless, their instability and low bioavailability make their administration through non parenteral routes very difficult, a fact that hampers their efficient exploitation in therapeutics. Since the 70´s, significant amount of research in the area of drug delivery and nanotechnology has been done with the final goal of overcoming those hurdles. In particular, biodegradable and biocompatible lipid and polymer-based nanocarriers have emerged as promising delivery platforms to enable the administration of proteins and peptides. This review provides an overview of the mostly explored nanotechnologies to date intended to produce lipidic and polymeric nanocarriers for protein/peptide delivery. The basic principles of the different techniques are discussed, and the main factors involved in the drug association and release, are analyzed. Finally, a brief overview of the potential applications of these protein/peptide-loaded nanocarriers, highlighting the nanomedicines that have reached the market or the clinical development phase, is provided.

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