Cooperative Self-Assembled Nanoparticle Induces Sequential Immunogenic Cell Death and Toll-Like Receptor Activation for Synergistic Chemo-immunotherapy

Abstract

Anticancer immunotherapy is hampered by poor immunogenicity and a profoundly immunosuppressive microenvironment in solid tumors and lymph nodes. Herein, sequential pH/redoxresponsive nanoparticles (SRNs) are engineered to activate the immune microenvironment of tumor sites and lymph nodes. The twomodular SRNs could sequentially respond to the acidic tumor microenvironment and endosome compartments of dendritic cells (DCs) to precisely deliver doxorubicin (DOX) and imidazoquinolines (IMDQs). In the tumor microenvironment, released DOX triggers immunogenic cell death. In sentinel lymph nodes, the IMDQ nanoparticle module is dissociated in the acidic endosome compartment to specifically stimulate toll-like receptor 7/8 for DC maturation. Thus, the orchestrated nanoparticle system could enhance the infiltration of CD8α + T cells in tumors and provoke a strong antitumor immune response toward primary and abscopal tumors in B16-OVA and CT26 tumor-bearing mice models. The cooperative self-assembled nanoparticle strategy provides a potential candidate of nanomedicine to advance the synergistic cancer chemo-immunotherapy.

Cascade-Responsive Hierarchical Nanosystems for Multisite Specific Drug Exposure and Boosted Chemoimmunotherapy

“…When the tumor volume reached 150 mm 3 , 200 μL of DiR-loaded MPH-NP (MPH-NP@DiR) was injected into mice via the tail veins at a DiR dosage of 5 μg/mouse (n = 3). At predetermined time intervals (1,12,24,36, or 48 h), the mice were anesthetized and the fluorescence images were acquired using an IVIS Lumina II system. The in vivo CD44 blocking experiment was performed by i.v.…”

“…Concretely, combination therapy surmounts the shortcomings of monotherapy and elicits synergistic (or called “1 + 1 > 2”) therapeutic benefits of two or more treatments. − Nowadays, the combination regimens of chemotherapy which involve the stimulation of antitumor immunity and immunotherapy have evaded the limitation of the low response rate of immunotherapy, and attracted widespread attention. − Specifically, nanomedicines incorporating chemotherapeutic drugs via physical or chemical interactions have greatly improved the therapeutic efficacy of the drugs and meanwhile reduced their toxic effects toward normal tissues, and have been developed to efficiently increase tumor immunogenicity. Hence, nano-based chemotherapy was frequently utilized to further combine with various immunotherapy strategies like immune checkpoint blockade (ICB) or indoleamine 2,3-dioxygenase (IDO) inhibitor for immune resistance alleviation, , immunostimulant cytokines for enhancing antitumor immunity, nanovaccine containing antigens and adjuvants for efficient antigen presentation to dendritic cells (DCs), as well as other treatments for reversal of tumor immunosuppression , and achieve synergistic and augmented therapeutic efficacy. For example, the combination of immune checkpoint inhibitor atezolizumab (a monoclonal antibody medication against PD-L1) with paclitaxel (PTX) protein-bound (Abraxane) was granted accelerated approval by the FDA in 2019 for treating patients with locally advanced or metastatic triple-negative breast cancer with PD-L1 expression, by virtue of the significant improvement in progression-free survival (PFS) in patients. , The clinical benefits of combination therapies are mostly attributed to the direct tumor cell killing by PTX and tumor immune attack through immune checkpoint blockade (ICB) of PD-1/PD-L1 axis augmented by PTX-incurred ICD. , Nevertheless, over 20% of patients receiving the above clinical regimen suffered from serious adverse events including peripheral neuropathies, alopecia, and vomiting. − …”

“…6−8 Specifically, nanomedicines incorporating chemotherapeutic drugs via physical or chemical interactions have greatly improved the therapeutic efficacy of the drugs and meanwhile reduced their toxic effects toward normal tissues, and have been developed to efficiently increase tumor immunogenicity. Hence, nano-based chemotherapy was frequently utilized to further combine with various immunotherapy strategies like immune checkpoint blockade (ICB) or indoleamine 2,3dioxygenase (IDO) inhibitor for immune resistance alleviation, 9,10 immunostimulant cytokines for enhancing antitumor immunity, 11 nanovaccine containing antigens and adjuvants for efficient antigen presentation to dendritic cells (DCs), 12 as well as other treatments for reversal of tumor immunosuppression 13,14 and achieve synergistic and augmented therapeutic efficacy. For example, the combination of immune checkpoint inhibitor atezolizumab (a monoclonal antibody medication against PD-L1) with paclitaxel (PTX) protein-bound (Abraxane) was granted accelerated approval by the FDA in 2019 for treating patients with locally advanced or metastatic triplenegative breast cancer with PD-L1 expression, by virtue of the significant improvement in progression-free survival (PFS) in patients.…”

Nanomedicine-enabled chemotherapy-based synergetic cancer treatments

“…Herein, Wang et al synthesized pH/redox responsive nanoparticles (SNRs) to co-activate the antigen exposure of tumor cells and the maturation of dendritic cells (DCs) in lymph nodes by sequentially inducing activation of ICD and toll-like receptor 7/8 (TLR7/8) for synergistic chemo-immunotherapy (Fig. 11 a) [ 64 ]. The prepared SRNs contain two functional modules of PC7A-ss-DOX and iPDPA-IMDQ, which are regarded as ICD-induction and immune stimulation module, respectively.…”

Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs

“…Chemoimmunotherapy has been developed into one of the most effective combination therapeutic strategies for the treatment of malignant cancer [ 12 , 13 ]. Chemotherapeutic drugs (such as DOX) can directly kill tumour cells and induce ICD to generate tumour antigens or danger signals; subsequently, the antitumour immune response can be induced by co-stimulation with tumour antigens and an ICI [ 14 , 15 ]. However, safe and effective targeted delivery of chemotherapeutic drugs remains challenging, in part because of poor bioavailability and non-specific targeting.…”