Theranostic nanoparticles with disease-specific administration strategies

Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H2O2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy.

Skin wound caused by external injury is usually difficult to be cured by conventional topical administration because of its poor drug diffusion across the stratum corneum. It has been recognized that stratum corneum is the major obstacle for transdermal drug delivery. To address this issue, microneedles (MNs) have been developed to penetrate the stratum corneum of the skin and then form micron-sized pores between the epidermis and the dermis layers. As such, biomacromolecule drugs and/or insoluble drug molecules can be allowed for effective transdermal penetration. A multifunctional microneedle array patch that can avoid wound infection and promote tissue remolding has important value for wound healing. Among others, marine polysaccharides have attracted much attention in multifarious biomedical applications due to their excellent (bio)physical and chemical properties. Herein, we developed a microneedle array patch using a blend of kangfuxin (KFX), chitosan (CS), and fucoidan (FD), named KCFMN, for accelerating full-thickness wound healing. The traditional Chinese medicine KFX extracted from Periplaneta americana (PA) has effective bio-functions in promoting wound healing. The macro-/micro-morphology and (bio)physicochemical properties of such composite microneedles were also studied. We showed that the KCFMN patch displayed noticeable antibacterial properties and good cytocompatibility. In particular, the KCFMN patch significantly accelerated the wound healing development in a full-thickness wound in rats by improving the epithelial thickness and collagen deposition. Thus, this versatile KCFMN patch has great prospects as a dressing for full-thickness wound healing.

https://www.frontiersin.org/articles/10.3389/fchem.2022.838920/pdf

Microneedle Array Patch Made of Kangfuxin/Chitosan/Fucoidan Complex Enables Full-Thickness Wound Healing

Diabetic wounds severely influence life, facing grand challenges in clinical treatments. The demand for better treatment is growing dramatically. Diabetic wound healing is challenging because of inflammation, angiogenesis disruptions, and tissue remodeling. Based on sequencing results of diabetic patients' skins and artificial intelligence (AI)-assisted bioinformatics, we excavate a potential therapeutic agent Trichostatin A (TSA) and a potential target histone deacetylase 4 (HDAC4) for diabetic wound healing. The molecular docking simulation reveals the favorable interaction between TSA and HDAC4. Taking advantage of the microneedle (MN) minimally invasive way to pierce the skin barrier for drug administration, we develop a swelling modified MN-mediated patch loaded with TSA to reduce the probability of injection-caused iatrogenic secondary damage. The MN-mediated TSA patch has been demonstrated to reduce inflammation, promote tissue regeneration, and inhibit HDAC4, which provides superior results in diabetic wound healing. We envisage that our explored specific drug TSA and the related MN-mediated drug delivery system can provide an innovative approach for diabetic wound treatment with simple, effective, and safe features and find a broad spectrum of applications in related biomedical fields.

Bowen Luo

Papers

Microneedle-Mediated Vaccination: Innovation and Translation.