Neutrophil-hitchhiking and bone-targeting ultrasound-responsive nanomodulators for synergistic immunogenic tumor inhibition and bone repair of bone metastasis.

Bone metastasis, a major contributor to skeletal complications in advanced cancers, poses a significant therapeutic challenge, largely attributable to poor drug delivery, self-perpetuating bone-tumor vicious cycle and severe bone damages. Herein, we engineered a multifunctional ultrasound (US)-responsive nanomodulator (SPNacs) through the co-assembly of a semiconducting polymer sonosensitizer (PF8DPP) and curcumin (Cur) with a reactive oxygen species (ROS)-cleavable polymer shell containing both bone and neutrophil dual-targeting ligands (alendronate and sialic acid). This design enabled a sequential targeting strategy, in which SPNacs first associated with circulating neutrophils for systemic transport and subsequent homing to bone metastatic niches via neutrophil-hitchhiking recruitment. Upon arrival at the metastatic sites, alendronate on the surface of SPNacs further exerted the second-step bone-targeting effect by chelating hydroxyapatite, thereby enhancing local retention and drug accumulation within the bone metastatic tumor microenvironment. External US irradiation activated this system to trigger the generation of cytotoxic ROS for tumor sonodynamic therapy and concurrently ruptured the ROS-cleavable polymer shell to accelerate the on-site release of Cur. The released Cur exerted as a modulator to alleviate the immunosuppressive state of the tumor microenvironment through downregulating programmed cell death ligand 1 (PD-L1) expression, while the Cur-mediated osteogenic effect combined with ALN-mediated osteoclast inhibition synergistically promoted bone repair. Consequently, a synergistic effect was achieved to simultaneously suppressed tumor progression and fostered bone tissue regeneration. Collectively, this study presents a promising therapeutic strategy that addresses both tumor eradication and skeletal repair within metastatic bone lesions.