Breakable Organosilica Nanocapsules for the Intracellular Delivery of a Peptide With Promising Anti‐Breast Cancer Activity

High-mobility group box 1 (HMGB1) is a protein acting as a regulator in tumor progression and therapy resistance, including breast cancer. HBP08-2, a novel HMGB1-inhibiting peptide, showed promising therapeutic potential; however, its poor stability and susceptibility to degradation limit cellular uptake. To overcome these limitations, a nanotechnology-based delivery system was developed using breakable organosilica nanocapsules designed to degrade under reducing intracellular conditions. Nanocapsules were synthesized through a microemulsion-assisted Stöber method and characterized by dynamic light scattering, transmission electron microscopy, and peptide quantification. They exhibited an encapsulation efficiency of 15.6%, a peptide content of 0.031 mg per mg of nanocapsules, and an average diameter of about 60 nm. In vitro studies demonstrated efficient internalization in MCF-7 and MDA-MB-231 breast cancer cells, with >99% sulfo-Cy5-positive cells after 3 and 6 h. Empty nanocapsules were nontoxic and biocompatible, while HBP08-2-loaded nanocapsules reduced cell viability by approximately 30% after 96 h. Coadministration with paclitaxel (PTX), a first-line chemotherapeutic, further enhanced the effect, reducing viability by up to 46.0% in MCF-7 and 43.4% in MDA-MB-231, suggesting that the combination of HBP08-2@CAPS and PTX may enhance cytotoxic activity compared with individual treatments. These findings support nanocapsules as a safe and versatile platform for intracellular peptide delivery and HMGB1-targeted strategies.