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The strategy of combining immune checkpoint inhibitors (ICIs) with anthracycline is recommended by clinical guidelines for the standard‐of‐care treatment of triple‐negative breast cancer (TNBC). Nevertheless, several fundamental clinical principles are yet to be elucidated to achieve a great therapeutic effect, including cancer‐homing delivery efficiency and ordinal‐interval regime. Tumor‐derived extracellular vesicles (TDEVs), as vectors for intratumoral intercellular communication, can encapsulate therapeutic agents and home tumors. However, PD‐L1 overexpression in TDEVs leads to systemic immunosuppression during in vivo circulation, ultimately inhibiting intratumoral T activity. In this study, CRISPR/Cas9‐edited Pd‐l1KO TDEV‐fusogenic anthracycline doxorubicin (DOX) liposomes with high drug encapsulation (97%) are fabricated, which homologously deliver DOX to breast cancer cells to intensify the immunogenic response and induce PD‐L1 overexpression in the tumor. By setting the stage for sensitizing tumors to ICIs, sequential treatment with disulfide‐linked PD1‐cross‐anchored TDEVs nanogels at one‐day interval could sustainably release PD1 in the tumor, triggering a high proportion of effector T cell‐mediated destruction of orthotopic and metastatic tumors without off‐target side effects in the 4T1‐bearing TNBC mouse model. Such a TDEV‐tandem‐augmented chemoimmunotherapeutic strategy with efficient cancer‐homing delivery capacity and optimized ordinal‐interval regime provides a solid foundation for developing chemoimmunotherapeutic formulations for TNBC therapy at the clinical level. [ABSTRACT FROM AUTHOR]

The schematic presentation illustrates the nanoassemblies for CPST. Initially, PTOX readily co-assembles with Ce6, forming a stable nanostructure. Subsequently, PEG2K is utilized as a PEG modifier to construct tumor-responsive nanoassemblies. Once endocytosed into tumor cells, these nanoassemblies rapidly disintegrate upon laser illumination, releasing PTOX and Ce6, thereby synergistically enhancing cancer therapy. [Display omitted] Chemo-photodynamic synergistic therapy (CPST) holds tremendous promise for treating cancers. Unfortunately, existing CPST applications suffer from complex synthetic procedures, low drug co-loading efficiency, and carrier-related toxicity. To address these issues, we have developed a supramolecular carrier-free self-sensitized nanoassemblies by co-assembling podophyllotoxin (PTOX) and chlorin e6 (Ce6) to enhance CPST efficiency against tumors. The nanoassemblies show stable co-assembly performance in simulative vivo neural environment (∼150 nm), with high co-loading ability for PTOX (72.2 wt%) and Ce6 (27.8 wt%). In vivo , the nanoassemblies demonstrate a remarkable ability to accumulate at tumor sites by leveraging the enhanced permeability and retention (EPR) effect. The disintegration of nanoassemblies following photosensitizer bioactivation triggered by the acidic tumor environment effectively resolves the challenge of aggregation-caused quenching (ACQ) effect. Upon exposure to external light stimulation, the disintegrated nanoassemblies not only illuminate cancer cells synergistically but also exert a more potent antitumor effect when compared with PTOX and Ce6 administered alone. This self-sensitized strategy represents a significant step forward in CPST, offering a unique co-delivery paradigm for clinic cancer treatment. [ABSTRACT FROM AUTHOR]

Off-targeting toxicity and immunosuppressive tumor microenvironment still restrict the therapeutic requirement of photodynamic therapy (PDT). The development of metal ion-coordination-based nanoparticles (NPs) for cancer therapy has advantages, such as precious nanostructure and potent therapeutic effect as well as great safety. In this study, we prepared calcium ions (Ca2+)-coordination photosensitizer NPs, based on Ca2+-pyrochloric acid (PPA)-coordination as the new photosensitive nanoamplifiers, and microneedles (MNs) as the personalized apparatus, and investigated the nanoamplifiers for treating the melanoma via transdermal administration. This nanoamplifiers was synthesized via a simple coordination of Ca2+ and PPA with the addition of bovine serum albumin (BSA), and further fabricated into MNs (nanoamplifiers@MNs). Following inserted into the tumor, the released nanoamplifiers from the tips and back layer exhibited great photodynamic activity under irradiation, inducing cancer cell death. Meanwhile, Ca2+ acted as the second messenger, promoting M1 polarization of macrophages and maturation of dendritic cells (DCs), thereby enhancing the immune activation effect in the tumor microenvironment. As a result, such nanoamplifiers effectively achieved significant efficacy against malignant melanoma tumors by synergistically tumor killing and potent anti-tumor immune activation without obviously side effect. This work demonstrated the potential of MNs-mediated metal ion-coordination-based nanoamplifier as a novel photodynamic therapeutic platform for the efficient and safe treatment of cancer. [ABSTRACT FROM AUTHOR]