No abstract

DNA is a perfect polymeric molecule for interfacing biology with material science to construct hydrogels that represent fascinating properties for a wide variety of biomedical applications. Tunable multifunctionality, convenient programmability, adequate biocompatibility, biodegradability, capability of precise molecular recognition, and high versatility have made DNA an irreplaceable building block for the construction of novel 3D hydrogels. DNA can be used as the only component of a hydrogel, the backbone or a cross-linker that connects the main building blocks to form hybrid hydrogels through chemical reactions or physical entanglement. Responsive constructs of DNA with superior mechanical properties are very commonly reported nowadays, which can undergo macroscopic changes induced by various triggers, including alteration in ionic strength, temperature, and pH. These hydrogels can be prepared by various types of DNA building blocks, such as branched double-stranded DNA, single-stranded DNA, X-shaped DNA, or Y-shaped DNA through intermolecular i-motif structures, DNA hybridization, enzyme ligation, or enzyme polymerization. These hydrogels are envisioned for a variety of applications, such as drug delivery, sensing, tissue engineering, 3D cell culture, and providing template for nanoparticle synthesis.

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The combination of chemo-and immunotherapy represents one promising strategy to overcome the existent challenges in the present-day anticancer therapy. Here, spermine-modified acetalated dextran nanoparticles (Sp-AcDEX NPs), co-loaded with the non-genotoxic molecule Nutlin-3a (Nut3a), and the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), are developed to induce cancer cell death and create a specific antitumor immune response. These polymeric NPs release Nut3a in a pH dependent fashion and induce endosomal escape. Due to Nut3a, the loaded NPs exert specific toxicity toward wild-type p53 cancer cells while avoiding toxicity in immune cells. Furthermore, the NPs show intrinsic immune adjuvancy on monocyte derived-dendritic cells, upregulating the expression of cell surface CD83 and CD86 costimulatory markers. Finally, it is examined that by inducing MCF-7 breast cancer cell death and acting as immune adjuvants, the NPs can downregulate the expression of IL-10 and upregulate IL-1β, leading to proliferation of CD3 + and cytotoxic CD8 + T cells. Overall, the study suggests that Sp-AcDEX NPs loaded with Nut3a and GM-CSF is a promising system for chemo-immunotherapy, capable of inducing tumor cell death and stimulating immune response.

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections.

Vaccination represents a promising strategy for cancer therapy due to its ability to efficiently eliminate tumors from the host body and prevent their recurrence. Nevertheless, the current vaccines are still lacking efficacy. Combination therapies, such as those integrating chemotherapy with immunotherapy, represent a powerful tool to potentially circumvent this drawback. Herein, injectable alginate cryogels loaded with granulocytemacrophage colony-stimulating factor and cytosine-phosphodiesterguanine-rich oligonucleotides, are combined with spermine-modified acetalated dextran nanoparticles (Sp-AcDEX NPs), loaded with p53 activator Nutlin-3a (Nut-3a) for combined chemoimmunotherapy. The Sp-AcDEX NPs are successfully loaded into the alginate cryogels and released over time. Furthermore, the delivery of the NPs from the cryogel enhances their accumulation in tumor tissue following peritumoral injection. Nut-3a exerts toxicity towards the tumor cells and induces immunogenic cell death through the upregulation of surface calreticulin expression. Overall, this combination is a promising strategy to reduce cancer cell proliferation, induce immunogenic cell death, and accumulate drug payloads into the tumor. This approach may avoid cancer recurrence through the induction of in situ cancer vaccination mediated by antigens and danger signals released from the apoptotic cancer cells.

Alteration of macrophage polarization from inflammatory (M1) to anti-inflammatory (M2) phenotype can have striking implications for the regeneration of injured tissues, treatment of inflammatory diseases, and relief of autoimmune disorders. Although certain cytokines like interleukin (IL)-4 and IL-13 are capable of inducing M2 macrophage polarization, their therapeutic potential in vivo is suffering from low efficacy due to their instability and poor access to target cells. Here, we report the synthesis of IL-4-loaded hyaluronic acid (HA) particle for the targeted delivery of cytokines through the high affinity of HA to CD44 receptors of macrophages. HA carriers composed of low, middle, and high molecular weight (MW) polymers were synthesized using divinyl sulfone (DVS) cross-linking. The MW of HA had a negligible effect on the physicochemical properties and biocompatibility of the macrophages, but as an indicative of M2 polarization, a significant change in the arginase-1 (Arg-1) activity, TNF-α release, and IL-10 secretion was observed for the HA particles prepared with high MW polymers. Therefore, these particles were loaded with IL-4 for simultaneous macrophage targeting and M1 to M2 reprogramming, evidenced by a remarkable increase in the Arg-1 to iNOS ratio, as well as CD163 and CD206 upregulation in the M1 macrophages, which were initially triggered by lipopolysaccharide and interferon-γ.

Immunotherapy is revolutionizing current therapies in cancer and in autoimmune diseases, showing impressive results in clinical trials. Recently, the development of innovative nano‐biomaterials has been focusing on the interactions between such materials and the immune system, both in the adaptive and innate branches. Biomaterials can display immunostimulative, neutral, or immunosuppressive interactions. Nanoparticles displaying immunostimulative potential are employed in the formulation of cancer vaccines, while immunosuppressive materials are being researched for the development of vaccines able to induce tolerance in autoimmune diseases. Here, the properties influencing the immunomodulation effect of nanomaterials are analyzed, followed by a detailed review of the recent applications of nanomaterials for the delivery of antigens, adjuvants, chemotherapeutics, and immunomodulatory drugs.