Supermolecular nanovehicles co-delivering TLR7/8-agonist and anti-CD47 siRNA for enhanced tumor immunotherapy.

Cancer immunotherapy is the most promising method for tumor therapy in recent years, among which the macrophages play a critical role in the antitumor immune response. However, tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype rather than the tumor-killing M1 phenotype. Moreover, the over-expressed CD47 on tumor cells severely hinders the function of macrophages by blocking the CD47/SIRPα pathway. Herein, a nano-assembly system of CHTR/siRNA was constructed through the host-guest interaction of a hyperbranched amino-functionalized ß-cyclodextrin and immune agonist imiquimod (R848), while CD47 siRNA was loaded inside through electrostatic interaction. The Toll-like receptor (TLR) 7/8 agonist R848 can "re-educate" macrophages from the protumoral M2 phenotype to antitumoral M1 phenotype, while CD47 siRNA can down-regulate the "don't eat me" CD47 signal on the surface of cancer cells and enhance the phagocytosis of cancer cells by macrophages. Through the dual regulation of TAMs, the immunosuppressive tumor microenvironment was relieved, and the host-guest drug-carrying system resulted in synergistic immunotherapy effect on tumors and inhibited tumor growth. The facile self-assembly of nanodrug offers a new strategy in co-delivery of multiple therapeutic agents for cascade cancer immunotherapy.

Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy.

The triple-negative breast cancer (TNBC) microenvironment makes a feature of aberrant vasculature, high interstitial pressure, and compact extracellular matrix, which combine to reduce the delivery and penetration of therapeutic agents, bringing about incomplete elimination of cancer cells. Herein, employing the tumor penetration strategy of size-shrinkage combined with ligand modification, we constructed a photothermal nanocluster for cascaded deep penetration in tumor parenchyma and efficient eradication of TNBC cells. In our approach, the photothermal agent indocyanine green (ICG) is laded in human serum albumin (HSA), which is cross-linked by a thermally labile azo linker (VA057) and then further modified with a tumor homing/penetrating tLyP-1 peptide (HP), resulting in a TNBC-targeting photothermal-responsive size-switchable albumin nanocluster (ICG@HSA-Azo-HP). Aided by the enhanced permeability and retention effect and guidance of HP, the ca. 149 nm nanoclusters selectively accumulate in the tumor site and then, upon mild irradiation with the 808 nm laser, disintegrate into 11 nm albumin fractions that possess enhanced intratumoral diffusion ability. Meanwhile, HP initiates the CendR pathway among the nutrient-deficient tumor cells and facilitates the transcellular delivery of the nanocluster and its disintegrated fractions for subsequent therapy. By employing this size-shrinkage and peptide-initiated transcytosis strategy, ICG@HSA-Azo-HP possesses excellent penetration capabilities and shows extensive penetration depth in three-dimensional multicellular tumor spheroids after irradiation. Moreover, with a superior photothermal conversion effect, the tumor-penetrating nanocluster can implement effective photothermal therapy throughout the tumor tissue under a second robust irradiation. Both in vivo orthotopic and ectopic TNBC therapy confirmed the efficient tumor inhibition of ICG@HSA-Azo-HP after dual-stage irradiation. The synergistic penetration strategy of on-demanded size-shrinkage and ligand guidance accompanied by clinically feasible NIR irradiation provides a promising approach for deep-penetrating TNBC therapy.

Construction of a Phenylboronic Acid-Functionalized Nano-Prodrug for pH-Responsive Emodin Delivery and Antibacterial Activity.

In this study, a pH-responsive nano-prodrug was fabricated by conjugating emodin to the PEGylated polyethyleneimine (mPEG-PEI) with acid-sensitive boronate ester bonds. 1H NMR spectra results showed that emodin was effectively bonded to mPEG-PEI, and acid-sensitive assay further confirmed the formation of boronate ester bonds. The size and morphology of the nano-prodrug were ascertained through transmission electron microscopy (TEM) and dynamic light scattering (DLS), which showed that the prodrug has a sphere-like shape with hydrodynamic size around 102 nm at pH 7.4. Subsequently, a drug-release behavior assay was carried out to carefully investigate the acid-sensitive drug-delivery property of the prodrug. Moreover, in vitro cell viability assay confirmed the superior cytotoxic effect of the nano-prodrug against HeLa cells compared to free emodin. Furthermore, the antibacterial study showed that the nano-prodrug could inhibit the bacterial (both Gram-positive and Gram-negative) growth more effectively than free emodin. Overall, this study provides a promising paradigm of the multifunctional nano-prodrug for pH-responsive tumor therapy and antibacterial activity.

Nanomedicine-based tumor photothermal therapy synergized immunotherapy.

The emerging anti-tumor immunotherapy has made significant progress in clinical application. However, single immunotherapy is not effective for all anti-tumor treatments, owing to the low objective response rate and the risk of immune-related side effects. Meanwhile, photothermal therapy (PTT) has attracted significant attention because of its non-invasiveness, spatiotemporal controllability and small side effects. Combining PTT with immunotherapy overcomes the issue that single photothermal therapy cannot eradicate tumors with metastasis and recurrence. However, it improves the therapeutic effect of immunotherapy, as the photothermal therapy usually promotes release of tumor-related antigens, triggers immune response by the immunogenic cell death (ICD), thereby, endowing unique synergistic mechanisms for cancer therapy. This review summarizes recent research advances in utilizing nanomedicines for PTT in combination with immunotherapy to improve the outcome of cancer treatment. The strategies include immunogenic cell death, immune agonists and cancer vaccines, immune checkpoint blockades and tumor specific monoclonal antibodies, and small-molecule immune inhibitors. The combination of synergized PTT-immunotherapy with other therapeutic strategies is also discussed.

Chain conformation transition induced host-guest assembly between triple helical curdlan and ß-CD for drug delivery.

The unique conformation transition from a triple helix to single coils for the triple helical ß-d-glucans has paved the way to fabricate various functional nanocomposites through the denaturing-renaturing process. This study firstly reports a novel kind of naturally derived supramolecular polymer micelle consisting of single-stranded chains of curdlan (CUR) and ß-CDs. It is proposed that ß-CDs as the host molecules were threaded onto single ß-glucan chains (denatured triplex CUR) via the host-guest interaction, thereby forming supramolecular micelles. The results from the 1H NMR, FT-IR, XRD and 2D 1H NOESY NMR studies confirmed the formation of the inclusion complex and the existence of the core-shell structure of the supramolecular assembly. TEM images and DLS revealed that the self-organized micelles displayed a regular spherical shape with an average diameter of ∼27 nm. Furthermore, the hydrophobic anticancer drug camptothecin (CPT) was selected as a model drug and successfully encapsulated into the CUR/ß-CD micelles. The drug-loaded micelles exhibited a steady sustained-release pattern regardless of the environmental pH. The flow cytometry and confocal laser scanning microscopy measurements confirmed that the CPT-loaded micelles could be well internalized into HepG 2 cells and continuously release the drug molecules inside the tumor cells. Meanwhile, the in vivo experiments demonstrated that CPT-loaded micelles could effectively inhibit tumor growth in comparison to free drugs. This concept will give a favorable platform to construct intelligent drug delivery systems for potential use.