Combined checkpoint blockade (e.g., PD1/PD-L1) with traditional clinical therapies can be hampered by side effects and low tumour-therapeutic outcome, hindering broad clinical translation. Here we report a combined tumour-therapeutic modality based on integrating nanosonosensitizers-augmented noninvasive sonodynamic therapy (SDT) with checkpoint-blockade immunotherapy. All components of the nanosonosensitizers (HMME/R837@Lip) are clinically approved, wherein liposomes act as carriers to co-encapsulate sonosensitizers (hematoporphyrin monomethyl ether (HMME)) and immune adjuvant (imiquimod (R837)). Using multiple tumour models, we demonstrate that combining nanosonosensitizers-augmented SDT with anti-PD-L1 induces an anti-tumour response, which not only arrests primary tumour progression, but also prevents lung metastasis. Furthermore, the combined treatment strategy offers a long-term immunological memory function, which can protect against tumour rechallenge after elimination of the initial tumours. Therefore, this work represents a proof-of-concept combinatorial tumour therapeutics based on noninvasive tumours-therapeutic modality with immunotherapy.

High intensity focused ultrasound (HIFU), as a promising and minimally invasive therapeutic modality against various solid tumors, has received considerable attention in the biomedical field. However, both the accuracy and efficacy of this technique are currently unsatisfactory. Herein, a nanometer-sized organic/inorganic hybrid enhancement agent for photoacoustic imaging (PAI)-guided HIFU therapy was designed and fabricated by concurrently encapsulating both Cu2-x S nanodots (NDs) and perfluorooctyl bromide (PFOB) into a poly(lactic-co-glycolic acid) PLGA nanocapsule (denoted CPPNs). These nanocapsules assumed a unique core/satellite/shell sandwich structure, and combined the merits of small and uniform particle size (about 120 nm), favorable biosafety, and multifunctional theranostic ability into one system. The high performance of Cu2-x S NDs in the absorption and conversion of near infrared laser confers high PAI contrast capability to the CPPNs, by which the location of the CPPNs within a tumor can be monitored successfully under PAI. Furthermore, our in vitro and in vivo results confirmed that the encapsulated PFOB in CPPNs increased the cavitation effect and thus enhanced the ablation efficacy under HIFU exposure. CPPNs show great potential as an efficient and powerful theranostic agent for future PAI-guided HIFU synergistic therapy.