A nanoagent for concurrent therapy of breast cancer bone metastasis and cancer-induced bone pain through SLC7A11 interruption and photodynamic therapy

Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.

Orchestrating antigen delivery and presentation efficiency in lymph node by nanoparticle shape for immune response

Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely unclear.Here,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas.Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes.On lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study.Interestingly,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study.These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.