The treatment of triple-negative breast cancer (TNBC) remains a challenging issue in clinical settings due to the absence of effective therapeutic targets. Recent studies have revealed that transient receptor potential vanilloid type 1 (TRPV1), a non-selective Ca2+ channel responsive to noxious thermal stimuli, is frequently overexpressed in both malignant breast cancers and vascular cells, expected to be a promising therapeutic target. Herein, we developed a second near-infrared (NIR-II) photothermal nanoplatform named CT@hCuS to enhance immunotherapy and exacerbate tumor starvation, constructed from hollow CuS nanoparticles (hCuS) with tannic acid (TA) surface-coating and efficient Ca2+ loading via stable TA/Ca2+ complexation. The CT@hCuS platform releases Ca2+ in response to the mildly acidic pH of the tumor microenvironment. When exposed to intermittent 1064 nm laser irradiation, CT@hCuS delivers precise and controllable photothermy while avoiding potential adverse events of chemical TRPV1 agonists, activating TRPV1 and initiating an intracellular influx of Ca2+, which could not only destroy tumor vessels but also induce the immunogenic death of tumor cells. The resulting tumor antigens can be captured by CT@hCuS through binding with TA, leading to in situ tumor vaccination. Moreover, the nanoplatform via local administration contributes to durable drug release. Both in vitro and in vivo experiments demonstrated that CT@hCuS, combined with intermittent NIR-II laser irradiation, significantly enhanced the synergistic effects of intracellular Ca2+ elevation for tumor vaccination and tumor vascular disruption, which not only selectively block tumor nutrient sources but also transforms the immunosuppressive tumor environment into an immunoreactive phenotype for inhibiting TNBC growth and metastasis. This work presents a powerful NIR-II photothermal nanoplatform and proposes a unique synergistic strategy of immunotherapy and vascular disruption therapy for clinical TNBC treatment.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(β-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Radiotherapy (RT) is one of the main clinical therapeutic strategies against cancer. Currently, multiple radiosensitizers aimed at enhancing X-ray absorption in cancer tissues have been developed, while limitations still exist for their further applications, such as poor cellular uptake, hypoxia-induced radioresistance, and unavoidable damage to adjacent normal body tissues. In order to address these problems, a cell-penetrating TAT peptide (YGRKKRRQRRRC)-modified nanohybrid was constructed by doping high-Z element Au in hollow semiconductor Cu2−xSe nanoparticles for combined RT and photothermal therapy (PTT) against breast cancer. The obtained Cu2−xSe nanoparticles possessed excellent radiosensitizing properties based on their particular band structures, and high photothermal conversion efficiency beneficial for tumor ablation and promoting RT efficacy. Further doping high-Z element Au deposited more high-energy radiation for better radiosensitizing performance. Conjugation of TAT peptides outside the constructed Cu2−xSe/Au nanoparticles facilitated their cellular uptake, thus reducing overdosage-induced side effects. This prepared multifunctional nanohybrid showed powerful suppression effects towards breast cancer, both in vitro and in vivo via integrating enhanced cell penetration and uptake, and combined RT/PTT strategies.

Phototherapies have many advantages for triple-negative breast cancer (TNBC) treatment. However, their effects are often limited by short blood circulation time, poor tumor selectivity and weak penetration of phototherapeutic agents, and tumor hypoxia. For overcoming these limitations, a versatile biomimetic system is developed based on red blood cells (RBCs). Photothermal agent new indocyanine green (IR820) is conjugated with the cell/tissue-penetrating TAT peptide and further efficiently encapsulated into the intact RBCs by crossing cell membranes to realize the long blood circulation. Meanwhile, cyclic RGD peptide (cRGD) is linked to the surfaces of RBCs through phospholipid insertion to obtain tumor vessel-targeting ability. Photosensitizer temoporfin (mTHPC) is next loaded into the membranes of RBCs by spontaneous transferring. The acquired biomimetic system (cRGD-RBC@mTHPC/TAT-IR820) exhibits potent photodynamic performance upon 652 nm laser irradiation with the facilitation of oxyhemoglobin, which could not only trigger TAT-IR820 release but also destroy tumor vessels. TAT-IR820 penetrates deeply into tumor tissue via the mediation of TAT peptide, exerting greatly promoted photothermal ablation against TNBC upon 808 nm laser irradiation. In situ generated tumor antigens further induce robust immune responses to suppress TNBC recurrence and metastasis. In summary, this study provides a versatile biomimetic system for comprehensive TNBC treatment via stepwise photodynamic and photothermal activations.