Transformation of nanoparticles into hydrogels for long-acting and sensitized apoptosis therapy of triple negative breast cancer

Despite the high sensitivity of triple-negative breast cancer (TNBC) to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy, its efficacy was limited by rapid systemic clearance and treatment tolerance. To overcome these barriers, we developed a pH-responsive nanoparticle-to-hydrogel system for long-lasting retention of TRAIL receptors at the tumour site and promoting apoptosis in TRAIL-sensitive TNBC cells. The nanoparticle core, composed of soluble TRAIL (sTRAIL) and terpyridine (TPY), was assembled <i>via</i> silk fibroin self-polymerization, while a metal-polyphenol (MPN) complexation structure imparts a pH-responsive outer shell. After peritumoral injection, the slightly acidic tumour microenvironment transiently degraded MPN, releasing dihydromyricetin (DMY) to upregulate the TRAIL receptor DR5, whereas Fe³⁺ covalently bound TPY, triggering nanoparticle-to-gel conversion. The system achieved a high DMY loading <i>via</i> the MPN network, rapidly released DMY under acidic tumour microenvironment conditions, and induced apoptotic receptor DR5 upregulation within 24 h. Dynamic covalent bond reconstitution converted nanoparticles into a hydrogel <i>in situ</i>, forming a stable library for sustained TRAIL release. Compared with conventional gels, this sequential fast-activation and continuous synergistic apoptosis strategy minimized burst release, extended TRAIL activity beyond six days, and localized the drug to the lesion area, increasing the local concentration of the drug while reducing systemic exposure. <i>In vitro</i> and <i>in vivo</i> studies confirmed enhanced apoptosis through dual-drug synergy with minimal systemic toxicity. This dynamic switching strategy delivery offers an innovative platform for protein-small molecule co-therapy, addressing TNBC resistance, and holds translational potential for clinical applications.