Regulation of mitochondrial apoptosis via siRNA-loaded metallo-alginate hydrogels: A localized and synergistic antitumor therapy

Preventing relapse after resection of a primary tumor continues to be an unmet clinical need. Development of adjuvant biomaterials with the capacity to kill residual cancer cells after tumor resection is of clinical importance. Here we developed a library of metallo-alginate hydrogels containing high concentrations of metallic ions such as Ca²⁺ in combination with Zn²⁺, Li⁺, or Mg²⁺ to disrupt Ca²⁺ homeostasis in the mitochondria of cancer cells by local hyperthermia. To synergistically kill tumor cells and suppress the growth of rechallenged tumors, we embedded oncogene-silencing nucleic acids (mTOR siRNA) loaded into polymerc nanoparticles (NPs) composed of poly (β-amino esters) in the metallo-alginate hydrogels, targeting cancer cells that activate multi-drug resistance pathways such PI3K/AKT/mTOR. Metabolomic studies showed alterations in the Warburg effect, mitochondrial transport, and the TCA cycle, confirming cancer cell damage. In vivo studies of this targeted therapy in mice demonstrated a sex-dependent effect. Male B16F10-tumor-bearing mice treated with the synergistic therapy showed restrained tumor growth. In contrast, no therapeutic effect was observed in female counterparts. Our results demonstrate that in situ-formed NP-loaded metallo-alginate hydrogels can modulate two distinct immune signaling networks that are relevant for enhancing cancer cell death. On the basis of our findings, this combination therapy emerges as a promising sex-dependent strategy for clinical translation.