bims-drudre 2022-08-21 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–08–21
seventeen papers selected by
Ceren Kimna, Technical University of Munich

Enhanced competition at the nano-bio interface enables comprehensive characterization of protein corona dynamics and deep coverage of proteomes.
Self-Assembled DNA-Protein Hybrid Nanospheres: Biocompatible Nano-Drug-Carriers for Targeted Cancer Therapy.
Engineered Bacterial Outer Membrane Vesicles as Controllable Two-way Adaptors to Activate Macrophage Phagocytosis for Improved Tumor Immunotherapy.
Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo.
A lipid nanoparticle platform for mRNA delivery through repurposing of cationic amphiphilic drugs.
Nanotechnology-based strategies against SARS-CoV-2 variants.
Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response.
Encapsulated bacteria deform lipid vesicles into flagellated swimmers.
Influence of Elasticity of Hydrogel Nanoparticles on Their Tumor Delivery.
Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy.
Helper-Polymer Based Five-Element Nanoparticles (FNPs) for Lung-Specific mRNA Delivery with Long-Term Stability after Lyophilization.
Electrospun patch delivery of anti-TNFα F(ab) for the treatment of inflammatory oral mucosal disease.
Conditional Antimicrobial Peptide Therapeutics.
A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.
Wireless Miniature Magnetic Phase-Change Soft Actuators.
Inorganic nanosheets facilitate humoral immunity against medical implant infections by modulating immune co-stimulatory pathways.
Integrated Three-dimensional Hydrophilicity/hydrophobicity Design for Artificial Sweating Skin (i-TRANS) Mimicking Human Body Perspiration.

Adv Mater. 2022 Aug 20. e2206008

Enhanced competition at the nano-bio interface enables comprehensive characterization of protein corona dynamics and deep coverage of proteomes.

Daniel Hornburg, Shadi Ferdosi, Alexey Stukalov, Moaraj Hasan, Behzad Tangeysh, Tristan R Brown, Tianyu Wang, Eltaher M Elgierari, Xiaoyan Zhao, Yingxiang Huang, Amir Alavi, Brittany Lee-McMullen, Jessica Chu, Mike Figa, Wei Tao, Jian Wang, Martin Goldberg, Evan S O'Brien, Hongwei Xia, Craig Stolarczyk, Ralph Weissleder, Vivek Farias, Serafim Batzoglou, Asim Siddiqui, Omid C Farokhzad.

  Introducing engineered nanoparticles (NPs) into a biofluid such as blood plasma leads to the formation of a selective and reproducible protein corona at the particle-protein interface, driven by the relationship between protein-NP affinity and protein abundance. We have developed a scalable system that leverages protein-nano interactions to overcome current limitations of deep plasma proteomics in large cohorts. Here we demonstrate the importance of the protein to NP-surface ratio (P/NP) and model protein corona formation dynamics, which determine the competition between proteins for binding. Tuning the P/NP ratio significantly modulates protein corona composition, enhancing depth and precision of a fully automated NP-based deep proteomic workflow (Proteograph ™). By increasing the binding competition on engineered NPs, we identify 1.2 - 1.7× more proteins with only 1% false discovery rate on the surface of each NP, and up to 3× compared to a standard plasma proteomics workflow. Moreover, our data suggests P/NP plays a significant role in determining the in vivo fate of nanomaterials in biomedical applications. Together, our study showcases the importance of P/NP as a key design element for biomaterials and nanomedicine in vivo and as a powerful tuning strategy for accurate, large-scale NP-based deep proteomic studies This article is protected by copyright. All rights reserved.

Keywords:  Machine learning; Mass spectrometry; Nano-bio interactions; Nanoparticles; Protein corona; Proteomics; Vroman effect

DOI:  https://doi.org/10.1002/adma.202206008
ACS Appl Mater Interfaces. 2022 Aug 15.

Self-Assembled DNA-Protein Hybrid Nanospheres: Biocompatible Nano-Drug-Carriers for Targeted Cancer Therapy.

Dayoung Lee, Seungki Baek, Young-Youb Kim, Yongbin Bang, Han Na Jung, Hyung-Jun Im, Yoon-Kyu Song.

  We developed hybrid nanospheres comprised of two of the most important biomolecules in nature, DNA and proteins, which have excellent biocompatibility, high drug payload capacity, in vivo imaging ability, and in vitro/in vivo cancer targeting capability. The synthesis can be done in a facile one-pot assembly system that includes three steps: step-growth polymerization of two DNA oligomers, addition of streptavidin to assemble spherical hybrid nanostructures, and functionalization of hybrid nanospheres with biotinylated aptamers. To test the feasibility of cancer targeting and drug-loading capacity of the hybrid nanospheres, MUC1-specific aptamers (MA3) were conjugated to nanosphere surfaces (apt-nanospheres), and doxorubicin (Dox) was loaded into nanospheres by DNA intercalation. The successful construction of nanospheres and apt-nanospheres was confirmed by agarose gel electrophoresis and dynamic light scattering (DLS). Their uniform spherical morphology was confirmed by transmission electron microscopy (TEM). Fluorescence spectra of nanospheres demonstrated high Dox-loading capability and slow-release characteristics. In vitro MUC1-specific binding of the apt-nanospheres was confirmed by flow cytometry and confocal microscopy. Dox-loaded apt-nanospheres significantly increased cytotoxicity of the MUC1-positive cancer cells due to aptamer-mediated selective internalization, as shown via cell viability assays. Apt-nanospheres could also be imaged in vivo through the synthesis of hybrid nanospheres using fluorescent dye-conjugated DNA strands. Finally, in vivo specific targeting ability of apt-nanospheres was confirmed in a MUC1-positive 4T1 tumor-bearing mouse model, whereas apt-nanospheres did not cause any sign of systemic toxicity in normal mice. Taken together, our self-assembled DNA-streptavidin hybrid nanospheres show promise as a biocompatible cancer targeting material for contemporary nanomedical technology.

Keywords:  DNA nanostructures; DNA−protein hybrid; cancer therapy; self-assembly; targeted drug delivery

DOI:  https://doi.org/10.1021/acsami.2c10397
Adv Mater. 2022 Aug 19. e2206200

Engineered Bacterial Outer Membrane Vesicles as Controllable Two-way Adaptors to Activate Macrophage Phagocytosis for Improved Tumor Immunotherapy.

Qingqing Feng, Xiaotu Ma, Keman Cheng, Guangna Liu, Yao Li, Yale Yue, Jie Liang, Lizhuo Zhang, Tianjiao Zhang, Xinwei Wang, Xiaoyu Gao, Guangjun Nie, Xiao Zhao.

  The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however re-education of macrophages remain a challenge. Bacteria-derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, we report an OMV-based controllable two-way adaptor, in which a CD47 nanobody (CD47nb) was fused onto OMV surface (OMV-CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV-CD47nb. The PEG/Se layer modification not only mitigated the immunogenicity of OMV-CD47nb, thereby remarkedly increasing the dose that could be administered safely through intravenous injection, but also equipped the formulation with radiation-triggered controlled release of OMV-CD47nb. Application of radiation to tumors in mice injected with the nanoformulation resulted in remodeling of TME. As two-way adaptors, OMV-CD47nb activated TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of "don't eat me" signal. Moreover, this activation of TAMs resulted in the stimulation of T cell-mediated antitumor immunity through effective antigen presentation. This article is protected by copyright. All rights reserved.

Keywords:  CD47; M1 polarization; outer membrane vesicles; tumor-associated macrophages; two-way adaptor

DOI:  https://doi.org/10.1002/adma.202206200
Nat Commun. 2022 Aug 15. 13(1): 4766

Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo.

Huanzhen Ni, Marine Z C Hatit, Kun Zhao, David Loughrey, Melissa P Lokugamage, Hannah E Peck, Ada Del Cid, Abinaya Muralidharan, YongTae Kim, Philip J Santangelo, James E Dahlman.

In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo.

DOI: https://doi.org/10.1038/s41467-022-32281-5
J Control Release. 2022 Aug 10. pii: S0168-3659(22)00514-4. [Epub ahead of print]

A lipid nanoparticle platform for mRNA delivery through repurposing of cationic amphiphilic drugs.

Bram Bogaert, Félix Sauvage, Roberta Guagliardo, Cristina Muntean, Van Phuc Nguyen, Eline Pottie, Mike Wels, An-Katrien Minnaert, Riet De Rycke, Qiangbing Yang, Dan Peer, Niek Sanders, Katrien Remaut, Yannis M Paulus, Christophe Stove, Stefaan C De Smedt, Koen Raemdonck.

  Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety- and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.

Keywords:  Cationic amphiphilic drugs; Cellular delivery; Drug repurposing; Lipid nanoparticles; Messenger RNA; Nanomedicine; RNA therapeutics

DOI:  https://doi.org/10.1016/j.jconrel.2022.08.009
Nat Nanotechnol. 2022 Aug 18.

Nanotechnology-based strategies against SARS-CoV-2 variants.

Xiangang Huang, Edo Kon, Xuexiang Han, Xingcai Zhang, Na Kong, Michael J Mitchell, Dan Peer, Wei Tao.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already infected more than 500 million people globally (as of May 2022), creating the coronavirus disease 2019 (COVID-19) pandemic. Nanotechnology has played a pivotal role in the fight against SARS-CoV-2 in various aspects, with the successful development of the two highly effective nanotechnology-based messenger RNA vaccines being the most profound. Despite the remarkable efficacy of mRNA vaccines against the original SARS-CoV-2 strain, hopes for quickly ending this pandemic have been dampened by the emerging SARS-CoV-2 variants, which have brought several new pandemic waves. Thus, novel strategies should be proposed to tackle the crisis presented by existing and emerging SARS-CoV-2 variants. Here, we discuss the SARS-CoV-2 variants from biological and immunological perspectives, and the rational design and development of novel and potential nanotechnology-based strategies to combat existing and possible future SARS-CoV-2 variants. The lessons learnt and design strategies developed from this battle against SARS-CoV-2 variants could also inspire innovation in the development of nanotechnology-based strategies for tackling other global infectious diseases and their future variants.

DOI: https://doi.org/10.1038/s41565-022-01174-5
Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2207841119

Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response.

Jinjin Chen, Zhongfeng Ye, Changfeng Huang, Min Qiu, Donghui Song, Yamin Li, Qiaobing Xu.

  The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8+ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180-188)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

Keywords:  cancer immunotherapy; lipid nanoparticles; lymph node-targeting mRNA delivery; mRNA vaccine; melanoma

DOI:  https://doi.org/10.1073/pnas.2207841119
Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2206096119

Encapsulated bacteria deform lipid vesicles into flagellated swimmers.

Lucas Le Nagard, Aidan T Brown, Angela Dawson, Vincent A Martinez, Wilson C K Poon, Margarita Staykova.

  We study a synthetic system of motile Escherichia coli bacteria encapsulated inside giant lipid vesicles. Forces exerted by the bacteria on the inner side of the membrane are sufficient to extrude membrane tubes filled with one or several bacteria. We show that a physical coupling between the membrane tube and the flagella of the enclosed cells transforms the tube into an effective helical flagellum propelling the vesicle. We develop a simple theoretical model to estimate the propulsive force from the speed of the vesicles and demonstrate the good efficiency of this coupling mechanism. Together, these results point to design principles for conferring motility to synthetic cells.

Keywords:  Escherichia coli; active matter; lipid vesicles; motile bacteria

DOI:  https://doi.org/10.1073/pnas.2206096119
Adv Sci (Weinh). 2022 Aug 18. e2202644

Influence of Elasticity of Hydrogel Nanoparticles on Their Tumor Delivery.

Xiangyu Chen, Shuwei Zhang, Jinming Li, Xiaobin Huang, Haochen Ye, Xuezhi Qiao, Zhenjie Xue, Wensheng Yang, Tie Wang.

  Polymeric nanocarriers have a broad range of clinical applications in recent years, but an inefficient delivery of polymeric nanocarriers to target tissues has always been a challenge. These results show that tuning the elasticity of hydrogel nanoparticles (HNPs) improves their delivery efficiency to tumors. Herein, a microfluidic system is constructed to evaluate cellular uptake of HNPs of different elasticity under flow conditions. It is found that soft HNPs are more efficiently taken up by cells than hard HNPs under flow conditions, owing to the greater adhesion between soft HNPs and cells. Furthermore, in vivo imaging reveals that soft HNPs have a more efficient tumor delivery than hard HNPs, and the greater targeting potential of soft HNPs is associated with both prolonged blood circulation and a high extent of cellular adhesion.

Keywords:  cellular adhesion; cellular uptake; flow conditions; soft hydrogel nanoparticles; tumor targeting

DOI:  https://doi.org/10.1002/advs.202202644
J Control Release. 2022 Aug 15. pii: S0168-3659(22)00524-7. [Epub ahead of print]

Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy.

Yuanyuan Shen, Mengni Hu, Wen Li, Yiling Chen, Yiluo Xu, Litao Sun, Dongzhe Liu, Siping Chen, Yueqing Gu, Yi Ma, Xin Chen.

  DNA nanostructures, with good biosafety, highly programmable assembly, flexible modification, and precise control, are tailored as drug carriers to deliver therapeutic agents for cancer therapy. However, they face considerable challenges regarding their delivery into the brain, mainly due to the blood-brain barrier (BBB). By controlling the acoustic parameters, focused ultrasound combined with microbubbles (FUS/MB) can temporarily, noninvasively, and reproducibly open the BBB in a localized region. We investigated the delivery outcome of pH-responsive DNA octahedra loading Epirubicin (Epr@DNA-Octa) via FUS/MB and its therapeutic efficiency in a mouse model bearing intracranial glioma xenograft. Using FUS/MB to locally disrupt the BBB or the blood-tumor barrier (BTB) and systemic administration of Epr@DNA-Octa (Epr@DNA-Octa + FUS/MB) (2 mg/kg of loaded Epr), we achieved an Epr concentration of 292.3 ± 10.1 ng/g tissue in glioma, a 4.4-fold increase compared to unsonicated animals (p < 0.001). The in vitro findings indicated that Epr released from DNA strands accumulated in lysosomes and induced enhanced cytotoxicity compared to free Epr. Further two-photon intravital imaging of spatiotemporal patterns of the DNA-Octa leakage revealed that the FUS/MB treatment enhanced DNA-Octa delivery across several physiological barriers at microscopic level, including the first extravasation across the BBB/BTB and then deep penetration into the glioma center and engulfment of DNA-Octa into the tumor cell body. Longitudinal in vivo bioluminescence imaging and histological analysis indicated that the intracranial glioma progression in nude mice treated with Epr@DNA-Octa + FUS/MB was effectively retarded compared to other groups. The beneficial effect on survival was most significant in the Epr@DNA-Octa + FUS/MB group, with a 50% increase in median survival and a 73% increase in the maximum survival compared to control animals. Our work demonstrates the potential viability of FUS/MB as an alternative strategy for glioma delivery of anticancer drugs using DNA nanostructures as the drug delivery platform for brain cancer therapy.

Keywords:  Blood-brain barrier; DNA nanostructure; Drug delivery; Focused ultrasound; Glioma

DOI:  https://doi.org/10.1016/j.jconrel.2022.08.019
Nano Lett. 2022 Aug 15.

Helper-Polymer Based Five-Element Nanoparticles (FNPs) for Lung-Specific mRNA Delivery with Long-Term Stability after Lyophilization.

Yan Cao, Zongxing He, Qimingxing Chen, Xiaoyan He, Lili Su, Wenxia Yu, Mingming Zhang, Huiying Yang, Xingxu Huang, Jianfeng Li.

  Lipid nanoparticles (LNPs) carrying therapeutic mRNAs hold great promise in treating lung-associated diseases like viral infections, tumors, and genetic disorders. However, because of their thermodynamically unstable nature, traditional LNPs carrying mRNAs need to be stored at low temperatures, which hinders their prevalence. Herein, an efficient lung-specific mRNA delivery platform named five-element nanoparticles (FNPs) is developed in which helper-polymer poly(β-amino esters) (PBAEs) and DOTAP are used in combination. The new strategy endows FNPs with high stability by increasing the charge repulsion between nanoparticles and the binding force of the aliphatic chains within the nanoparticles. The structure-activity relationship (SAR) shows that PBAEs with E1 end-caps, higher degrees of polymerization, and longer alkyl side chains exhibit higher hit rates. Lyophilized FNP formulations can be stably stored at 4 °C for at least 6 months. Overall, a novel delivery platform with high efficiency, specificity, and stability was developed for advancing mRNA-based therapies for lung-associated diseases.

Keywords:  five-element nanoparticles; lung-specific; lyophilization; poly(β-amino esters); stability

DOI:  https://doi.org/10.1021/acs.nanolett.2c01784
J Control Release. 2022 Aug 13. pii: S0168-3659(22)00520-X. [Epub ahead of print]

Electrospun patch delivery of anti-TNFα F(ab) for the treatment of inflammatory oral mucosal disease.

Jake G Edmans, Bethany Ollington, Helen E Colley, Martin E Santocildes-Romero, Lars Siim Madsen, Paul V Hatton, Sebastian G Spain, Craig Murdoch.

  Chronic ulcerative oral mucosal inflammatory diseases, including oral lichen planus and recurrent aphthous stomatitis, are painful and highly prevalent, yet lack effective clinical management. In recent years, systemic biologic therapies, including monoclonal antibodies that block the activity of cytokines, have been increasingly used to treat a range of immune-mediated inflammatory conditions such as rheumatoid arthritis and psoriasis. The ability to deliver similar therapeutic agents locally to the oral epithelium could radically alter treatment options for oral mucosal inflammatory diseases, where pro-inflammatory cytokines, in particular tumour-necrosis factor-α (TNFα), are major drivers of pathogenesis. To address this, an electrospun dual-layer mucoadhesive patch comprising medical-grade polymers was investigated for the delivery of F(ab) biologics to the oral mucosa. A fluorescent-labelled F(ab) was incorporated into mucoadhesive membranes using electrospinning with 97% v/v ethanol as a solvent. The F(ab) was detected within the fibres in aggregates when visualised by confocal microscopy. Biotinylated F(ab) was rapidly eluted from the patch (97 ± 5% released within 3 h) without loss of antigen-binding activity. Patches applied to oral epithelium models successfully delivered the F(ab), with fluorescent F(ab) observed within the tissue and 5.1 ± 1.5% cumulative transepithelial permeation reached after 9 h. Neutralising anti-TNFα F(ab) fragments were generated from whole IgG by papain cleavage, as confirmed by SDS-PAGE, then incorporated into patches. F(ab)-containing patches had TNFα neutralising activity, as shown by the suppression of TNFα-mediated CXCL8 release from oral keratinocytes cultured as monolayers. Patches were applied to lipopolysaccharide-stimulated immune-competent oral mucosal ulcer equivalents that contained primary macrophages. Anti-TNFα patch treatment led to reduced levels of active TNFα along with a reduction in the levels of disease-implicated T-cell chemokines (CCL3, CCL5, and CXCL10) to baseline concentrations. This is the first report of an effective device for the delivery of antibody-based biologics to the oral mucosa, enabling the future development of new therapeutic strategies to treat painful conditions.

Keywords:  Antibodies; Drug delivery; Electrospinning; Oral medicine; Oral patches; TNFα

DOI:  https://doi.org/10.1016/j.jconrel.2022.08.016
ACS Nano. 2022 Aug 18.

Conditional Antimicrobial Peptide Therapeutics.

Chayanon Ngambenjawong, Leslie W Chan, Heather E Fleming, Sangeeta N Bhatia.

  Antimicrobial peptides (AMPs) constitute a promising class of alternatives to antibiotics to curb antimicrobial resistance. Nonetheless, their utility as a systemic agent is hampered by short circulation time and toxicity. Infection sites, analogous to tumors, harbor an aberrant microenvironment that has the potential to be exploited to develop conditionally activated therapeutics with an improved therapeutic index. In particular, we identified strategies to prolong systemic circulation of small, cationic AMPs in a mouse model of bacterial pneumonia. Specifically, we report an albumin-binding domain (ABD)-AMP conjugate as a long-circulating conditional AMP therapeutic with a masked activity that can be liberated by proteases in the infected tissue microenvironment. Our systemically administered conjugate enhanced the pulmonary delivery of active AMP while also reducing AMP exposure to other off-target organs. Importantly, this reduction in off-target exposure improved the safety profile of the AMP. The framework we present can be generalized to quantify and optimize the performance of this emerging class of conditional therapeutics.

Keywords:  albumin; antimicrobial peptide; conditional therapeutic; infection; nanomedicine; protease

DOI:  https://doi.org/10.1021/acsnano.2c04162
Nat Commun. 2022 Aug 17. 13(1): 4829

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.

Manijeh Goldberg, Aaron Manzi, Peter Conway, Stefanie Cantin, Vasudha Mishra, Alka Singh, Alexander T Pearson, Eric R Goldberg, Sam Goldberger, Benjamin Flaum, Rifat Hasina, Nyall R London, Gary L Gallia, Chetan Bettegowda, Sonya E O'Neill, Erkin Aydin, Alex Zhavoronkov, Anxo Vidal, Atenea Soto, Maria Jose Alonso, Ari J Rosenberg, Mark W Lingen, Anil D'Cruz, Nishant Agrawal, Evgeny Izumchenko.

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

DOI: https://doi.org/10.1038/s41467-022-31859-3
Adv Mater. 2022 Aug 17. e2204185

Wireless Miniature Magnetic Phase-Change Soft Actuators.

Yichao Tang, Mingtong Li, Tianlu Wang, Xiaoguang Dong, Wenqi Hu, Metin Sitti.

  Wireless miniature soft actuators are promising for various potential high-impact applications in medical, robotic grippers, and artificial muscles. However, these miniature soft actuators are currently constrained by a small output force and low work capacity. To address such challenges, we report a miniature magnetic phase-change soft composite actuator. This soft actuator exhibits an expanding deformation and enables up to a 70 N output force and 175.2 J/g work capacity under remote magnetic radio frequency heating, which are 106 -107 times that of traditional magnetic soft actuators. To demonstrate its capabilities, we first design a wireless soft robotic device that can withstand 0.24 m/s fluid flows in an artery phantom. By integrating it with a thermally-responsive shape-memory polymer and bistable metamaterial sleeve, we design a wireless reversible bistable stent towards for future potential angioplasty applications. Moreover, it can additionally locomote inside and jump out of granular media. At last, the phase-change actuator can realize programmable bending deformations when a specifically designed magnetization profile is encoded, enhancing its shape-programming capability. Such a miniature soft actuator provides an approach to enhance the mechanical output and versatility of magnetic soft robots and devices, extending their medical and other potential applications. This article is protected by copyright. All rights reserved.

Keywords:  high work capacity; magnetic soft composites; miniature wireless soft device; phase-change materials; programmable shape deformation

DOI:  https://doi.org/10.1002/adma.202204185
Nat Commun. 2022 Aug 18. 13(1): 4866

Inorganic nanosheets facilitate humoral immunity against medical implant infections by modulating immune co-stimulatory pathways.

Chuang Yang, Yao Luo, Hao Shen, Min Ge, Jin Tang, Qiaojie Wang, Han Lin, Jianlin Shi, Xianlong Zhang.

Strategies to manipulate immune cell co-inhibitory or co-activating signals have revolutionized immunotherapy. However, certain immunologically cold diseases, such as bacterial biofilm infections of medical implants are hard to target due to the complexity of the immune co-stimulatory pathways involved. Here we show that two-dimensional manganese chalcogenophosphates MnPSe3 (MPS) nanosheets modified with polyvinylpyrrolidone (PVP) are capable of triggering a strong anti-bacterial biofilm humoral immunity in a mouse model of surgical implant infection via modulating antigen presentation and costimulatory molecule expression in the infectious microenvironment (IME). Mechanistically, the PVP-modified MPS (MPS-PVP) damages the structure of the biofilm which results in antigen exposure by generating reactive oxidative species, while changing the balance of immune-inhibitory (IL4I1 and CD206) and co-activator signals (CD40, CD80 and CD69). This leads to amplified APC priming and antigen presentation, resulting in biofilm-specific humoral immune and memory responses. In our work, we demonstrate that pre-surgical neoadjuvant immunotherapy utilizing MPS-PVP successfully mitigates residual and recurrent infections following removal of the infected implants. This study thus offers an alternative to replace antibiotics against hard-to-treat biofilm infections.

DOI: https://doi.org/10.1038/s41467-022-32405-x
Adv Mater. 2022 Aug 17. e2204168

Integrated Three-dimensional Hydrophilicity/hydrophobicity Design for Artificial Sweating Skin (i-TRANS) Mimicking Human Body Perspiration.

Yucan Peng, Jiawei Zhou, Yufei Yang, Jian-Cheng Lai, Yusheng Ye, Yi Cui.

  Artificial skins reproducing properties of human skin are emerging and significant for study in various areas, such as robotics, medicine, textiles, etc. Perspiration, as one of the most imperative thermoregulation functions of human skin, is gaining increasing attention, but how to realize ideal artificial skin for perspiration simulation remains challenging. Here, we propose an integrated three-dimensional hydrophilicity/hydrophobicity design for artificial sweating skin (i-TRANS). Based on normal fibrous wicking materials, the selective surface modification with gradient of Polydimethylsiloxane (PDMS) creates hydrophilicity/hydrophobicity contrast in both lateral and vertical directions. With the additional help of bottom hydrophilic Nylon 6 nanofibers, the constructed i-TRANS is able to transport "sweat" directionally without trapping undesired excess water and attain uniform "secretion" of sweat droplets on the top surface, decently mimicking human skin perspiration situation. This fairly comparable simulation not only presents new insights for replicating skin properties, but also provides proper in vitro testing platforms for perspiration-relevant research, greatly avoiding unwanted interference from the "skin" layer. In addition, the facile, fast and cost-effective fabrication approach and versatile usage of i-TRANS can further facilitate its application. This article is protected by copyright. All rights reserved.

Keywords:  artificial skin; perspiration mimicking; surface hydrophilicity/hydrophobicity; surface modification; textile

DOI:  https://doi.org/10.1002/adma.202204168