Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)‐associated danger‐associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo‐Ce6/TPZ@MH) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia‐activated tirapazamine (TPZ) in the red blood cells–PLTs hybrid membrane (MH)‐camouflaged pH‐sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high‐effective synergistic therapy. Meanwhile, DAMPs‐mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet‐mediated metastasis. In addition, ICD‐mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis.

Efficient cancer vaccines not only require the co-delivery of potent antigens and highly immunostimulatory adjuvants to initiate robust tumor-specific host immune response but also solve the spatiotemporal consistency of host immunity and tumor microenvironment (TME) immunomodulation. Here, we designed a biomaterials-based strategy for converting tumor-derived antigenic microparticles (T-MPs) into a cancer vaccine to meet this conundrum and demonstrated its therapeutic potential in multiple murine tumor models. The internal cavity of T-MPs was employed to store nano-Fe3O4 (Fe3O4/T-MPs), and then dense adjuvant CpG-loaded liposome arrays (CpG/Lipo) were tethered on the surface of Fe3O4/T-MP through mild surface engineering to get a vaccine (Fe3O4/T-MPs-CpG/Lipo), demonstrating that co-delivery of Fe3O4/T-MPs and CpG/Lipo to antigen presenting cells (APCs) could elicit strong tumor antigen-specific host immune response. Meanwhile, vaccines distributed in the TME could reverse infiltrated tumor-associated macrophages into a tumor-suppressive M1 phenotype by nano-Fe3O4, amazingly induce abundant infiltration of cytotoxic T lymphocytes, and transform a “cold” tumor into a “hot” tumor. Furthermore, amplified antitumor immunity was realized by the combination of an Fe3O4/T-MPs-CpG/Lipo vaccine and immune checkpoint PD-L1 blockade, specifically inhibiting ∼83% of the progression of B16F10-bearing mice and extending the median survival time to 3 months. Overall, this study synergistically modulates the tumor immunosuppressive network and host antitumor immunity in a spatiotemporal manner, which suggests a general cell-engineering strategy tailored to a personalized vaccine from autologous cancer cell materials of each individual patient.

Despite the potential of drug‐loaded scaffolds for tumor recurrence and metastasis (TRM) postoperation, their therapeutic benefits are limited by marked immunosuppressive tumor microenvironment (ITME) and drug‐related untargeted toxicity. Herein, an innovative implantable bioresponsive nanoarray is developed to overcome the above limitations. Chemotherapeutics doxorubicin (DOX) and the epigenetic modulator JQ1 are coloaded into tumor‐targeting nanoparticles (HP‐DOX/JQ1 NPs), which are then linked up through a bio‐responsive linker to construct the nanoarray loading with another part of JQ1 (DOX/JQ1‐IBRN). Under high level of H2O2 in TME, the implanted DOX/JQ1‐IBRN disaggregates and release JQ1 while generating small‐sized HP‐DOX/JQ1 NPs for realizing ITME modulation and tumor‐targeting therapy. JQ1 selectively blocks programmed death‐ligand 1 (PD‐L1) mediated immune evasion and reduces regulatory T cells (Tregs)/‐disruptive effect to facilitate immunopositivity. HP‐DOX/JQ1 NPs destroy residual tumor precisely and trigger gasdermin E (GSDME)‐dependent pyroptosis, further enhancing the number and functions of tumor‐infiltrating T lymphocytes for antitumor immunity. It is demonstrated that DOX/JQ1‐IBRN prevents post‐surgical TRM and prolongs survival in multiple murine tumor models with negligible toxicity. This cooperation in tumor accurate pyroptosis and ITME conversion through the implantable nanoarray (a simple, valid, and safe scaffold) is expected to provide crucial insights for post‐surgical treatment.

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