Multi-responsive hydrogels with dual-dynamic covalent and hydrogen-bonded networks: Aldehyde-functionalised silica reinforced β-cyclodextrin/hyaluronic acid frameworks for enhanced breast cancer therapy and inflammation suppression.

In recent years, double dynamic bond-based hydrogels have attracted extensive attention in tumour treatment due to their multiple responses to tumour microenvironment (e.g., pH, GSH, temperature), which significantly improve treatment accuracy and efficacy. By means of dual-dynamic covalent and hydrogen-bonded networks, we designed a multi-responsive hydrogel (HDPCC) which was constructed by oxidised hyaluronic acid (HA-Cys), oxidised β-cyclodextrin including curcumin (OXβ-CD/CUR) and aldehyde functionalized silica loaded with paclitaxel (DMO-CHO/PTX) via disulfide (-S-S-) and imine (-CH=N-) bonds. Systematic characterisation of rheological properties, in vitro drug release behaviour and anti-tumour effect demonstrated that the HDPCC significantly inhibited tumour growth (3.774 ± 0.744) compared with free drugs. This was attributed to HA-Cys targeting of the CD44 receptor, glutathione response, and pH sensitivity in tumour microenvironment. GSH concentrations of 1, 5, and 10 mM have corresponding PTX release of 29.4 %, 31.0 % and 32.7 %, respectively. At 48 h, cumulative PTX release percentages were 22.1 % (pH 7.4), 25.3 % (pH 6.5), and 28.5 % (pH 5.5). DMO-CHO/PTX and OXβ-CD/CUR inclusion complex reinforced the stability of hydrogel skeleton, accompanied by anti-inflammatory CUR effect. Cell viability and animal experiments demonstrated that HDPCC had excellent biocompatibility, high biodegradability, high apoptosis rate (27.7 %), and strong cell inhibitory ability (cell viability was 30.987 ± 2.918). Our findings provide a new strategy for developing intelligent and responsive anti-tumour delivery systems.