Search

Cancer vaccines show promise by eliciting tumor-specific cytotoxic T lymphocytes (CTL) responses. Efficient cytosolic co-delivery of antigens and adjuvants to dendritic cells (DCs) is crucial for vaccines to induce anti-tumor immunity. However, peptide- or nucleic acid-based biomolecules like tumor antigens and STING agonist cyclic-di-GMP (cdGMP) are prone to endosomal degradation, resulting in low cytosolic delivery and CTL response rates. Cationic nanocarriers can improve cytosolic delivery, but their positive charges induce off-target effects. Here, we develop cationic poly(ester amide) based nanoparticles co-loaded with antigens and adjuvant cdGMP (NP(cG, OVA)) for efficient cytosolic delivery and swallow them within antigen self-presenting DCs-derived dendrosomes (ODs) for lymph nodes (LNs) homing. The constructed dendrosomes swallowing nanovaccines ODs/NP(cG, OVA) demonstrated significantly reduced liver accumulation and enhanced LNs and DCs targeting compared to NP(cG, OVA). ODs/NP(cG, OVA) effectively cross-dressed the antigen epitopes on the shell to DCs and facilitated internalization of NP(cG, OVA), realizing DCs cytosolic co-delivery of antigens and adjuvants, thereby promoting antigen presentation, maturation and inflammatory cytokines secretion of DCs. Consequently, DCs stimulated by ODs/NP(cG, OVA) effectively induced activation, proliferation, and differentiation of antigen-specific CTLs that provided robust immune protection against tumor invasion. This work presents a powerful vaccine strategy for cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l-DOPA induced dyskinesia (LID), which is the debilitating side effect of l-DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l-DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immunotherapy is regarded as one of the most promising approaches for treating tumors, with a multitude of immunotherapeutic thoughts currently under consideration for the lethal glioblastoma (GBM). However, issues with immunotherapeutic agents, such as limited in vivo stability, poor blood-brain barrier (BBB) penetration, insufficient GBM targeting, and represented monotherapy, have hindered the success of immunotherapeutic interventions. Moreover, even with the aid of conventional drug delivery systems, outcomes remain suboptimal. Biomimetic strategies seek to overcome these formidable drug delivery challenges by emulating nature's intelligent structures and functions. Leveraging the variety of biological structures and functions, biomimetic drug delivery systems afford a versatile platform with enhanced biocompatibility for the co-delivery of diverse immunotherapeutic agents. Moreover, their inherent capacity to traverse the BBB and home in on GBM holds promise for augmenting the efficacy of GBM immunotherapy. Thus, this review begins by revisiting the various thoughts and agents on immunotherapy for GBM. Then, the barriers to successful GBM immunotherapy are analyzed, and the corresponding biomimetic strategies are explored from the perspective of function and structure. Finally, the clinical translation's current state and prospects of biomimetic strategy are addressed. This review aspires to provide fresh perspectives on the advancement of immunotherapy for GBM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Obesity is a major public burden on the working population and induces chronic diseases. Its treatment often requires long-term medication, which makes patient compliance difficult. In this study, we reported the value of HORN-MN, which comprised a fast-soluble hyaluronic acid microneedle matrix and a weak acid-degradable oleanolic acid dimer of rosiglitazone nanoparticles. The results showed that the microneedles easily punctured the stratum corneum and dissolved in the dermis of the abdominal wall within 5 min, followed by the release of rosiglitazone nanoparticles. Thereafter, the nanoparticles were endocytosed by macrophages and white adipocytes, then degraded to oleanolic acid in the lysosomes, thereby, releasing rosiglitazone. Oleanolic acid significantly improved the inflammatory status of obese adipose tissue and promoted white adipocyte browning, and rosiglitazone significantly potentiated WAC browning. Accordingly, the patch demonstrated a remarkable obesity-reducing efficacy in mice. In conclusion, this study developed a quick paster type of soluble rosiglitazone nanoparticle microneedle for the treatment of obesity. This patch can be suitable for working people, with an evident obesity-reducing efficacy but no effect on skin integrity despite multiple administrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dendritic cells (DCs) activation is crucial for regulating the antitumor immune response. However, the tumor's immunosuppressive environment significantly impedes antigen presentation and DCs maturation, thereby limiting the effectiveness of cancer immunotherapy. To address this challenge, we developed tumor cell membrane-coated covalent organic framework (COF) nanoparticles, loaded with mannose-modified gold nanoparticles and doxorubicin (Dox). This created a cell membrane-camouflaged COF-based nanosatellite designed to enhance tumor-targeted chemoimmunotherapy. The nanosatellite exhibits distinct photothermal properties and releases Dox in a pH-sensitive manner, targeting tumor cells to induce immunogenic cell death (ICD) and expose a wealth of antigens. Crucially, the COF structure is selectively degraded to release mannose-modified gold nanoparticles in the acidic environment. These nanoparticles capture antigens from the ICD and efficiently transport them to lymph nodes rich in DCs, facilitated by mannose receptor mediation. As a result, antigens are effectively presented to DCs, activating the immune response, significantly hindering tumor growth and lung metastasis in mice, and extending survival. This study pioneered innovative nano-preparations aimed at enhancing tumor immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ferroptosis has been recognized as a promising therapeutic strategy for cancer due to its unique mechanism of action. However, the upregulation of stearoyl-CoA desaturase 1 (SCD1) in ovarian cancer leads to resistance to ferroptotic therapy. Zinc ion (Zn 2+ ) serves as the cofactor of SCD1. It was hypothesized that selective deprivation of Zn 2+ from SCD1 could sensitize ferroptotic ovarian cancer therapy. Here, we report a hypoxia-responsive polymer micelle for enhanced ferroptosis of ovarian cancer cells. A SCD1 inhibitor, PluriSIn 1 (Plu), and a ferroptosis inducer, Auranofin (Aur), were co-encapsulated in nitroimidazole-bearing micelles. Under the hypoxic tumor microenvironment, the conversion of nitroimidazole to aminoimidazole triggered the cargo release and induced the depletion of antioxidant molecules (e.g., glutathione, thioredoxin, and NADPH). Meanwhile, because of the strong coordination between aminoimidazole and Zn 2+ compared to that of histidine and Zn 2+ , such conversion can deprive the metal cofactor of SCD1, hence sensitizing the action of Plu and Aur. The proof-of-concept was demonstrated in cell and animal models with minimal systemic toxicity. The current work integrates ferroptosis induction with SCD1 inhibition in a hypoxia-responsive vehicle, offering a promising strategy for addressing the ferroptosis resistance and opening novel avenues for managing the difficult-to-treat ovarian cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hypertrophic scar (HS) tends to raised above skin level with high inflammatory microenvironment and excessive proliferation of myofibroblasts. The HS therapy remains challenging due to dense scar tissue which makes it hard to penetrate, and the side effects resulting from intralesional corticosteroid injection which is the mainstay treatment in clinic. Herein, bilayer microneedle patches combined with dexamethasone and colchicine (DC-MNs) with differential dual-release pattern is designed. Two drugs loaded in commercially available materials HA and PLGA, respectively. Specifically, after administration, outer layer rapidly releases the anti-inflammatory drug dexamethasone, which inhibits macrophage polarization to pro-inflammatory phenotype in scar tissue. Subsequently, inner layer degrades sustainedly, releasing antimicrotubular agent colchicine, which suppresses the overproliferation of myofibroblasts with extremely narrow therapeutic window, and inhibits the overexpression of collagen, as well as promotes the regular arrangement of collagen. Only applied once, DC-MNs directly delivered drugs to the scar tissue. Compared to traditional treatment regimen, DC-MNs significantly suppressed HS at lower dosage and frequency by differential dual-release design. Therefore, this study put forward the idea of integrated DC-MNs accompany the development of HS, providing a non-invasive, self-applicable, more efficient and secure strategy for treatment of HS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jonathan S. Serody reports financial support was provided by ROI Grant from the State of North Carolina. Jonathan S. Serody reports financial support was provided by NCI Breast SPORE program (P50-CA058223). Mostafa Yazdimamaghani reports financial support was provided by Basic Immune Mechanisms Training Program (NIH T32AI007273). Mostafa Yazdimamaghani reports financial support was provided by Carolina Cancer Nanotechnology Training Program (NIH T32CA196589). Alexander V. Kabanov reports financial support was provided by TTNCI (NIH R01 CA2644488). Charles M. Perou reports financial support was provided by RO1-CA148761. Alexander V. Kabanov reports a relationship with DelAqua Pharmaceuticals Inc that includes: board membership and equity or stocks. Alexander V. Kabanov reports a relationship with SoftKemo Pharma Corp that includes: board membership and equity or stocks. Alexander V. Kabanov reports a relationship with BendaRx Pharma Corp that includes: board membership and equity or stocks. Jonathan S. Serody reports a relationship with Merck Inc that includes: funding grants. Jonathan S. Serody reports a relationship with Carisma Therapeutics that includes: funding grants. Charles M. Perou reports a relationship with BioClassifier LLC that includes: consulting or advisory and equity or stocks. Jonathan S. Serody has patent #Innate immune stimulators to enhance CAR T cell activity in solid tumors and for the use of lymphodepletion and CD30.CAR T cells for patients with Hodgkin Lymphoma licensed to Tessa Therapeutics. Charles M. Perou has patent #Breast PAM50 Subtyping assay with royalties paid to BioClassifier. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nondestructive penetration of the blood-brain barrier (BBB) to specifically prevent iron deposition and the generation of reactive oxygen species (ROS) shows great potential for treating Parkinson's disease (PD). However, effective agents with distinct mechanisms of action remain scarce. Herein, a N-doping carbon dot (CD) emitting red light was prepared, which can sacrifice ROS and produce nitric oxide (NO) owing to its surface N-involved groups conjugated to the sp 2 -hybrided π-system. Meanwhile, CD can chelate iron ions, thus depressing the catalytic Fe cycle and *OH detaching to inhibit the Fenton reaction. By modifying lactoferrin (Lf) via polyethylene glycol (PEG), the resulting CD-PEG-Lf (CPL) can nondestructively cross the BBB, targeting the dopaminergic neurons via both NO-mediated reversible BBB opening and Lf receptor-mediated transportation. Accordingly, it can serve as an antioxidant, reducing oxidative stress via its unique iron chelation, free radical sacrificing, and synergy with iron reflux prevention originating from Lf. Thus, it can significantly reduce brain inflammation and improve the behavioral performance of PD mice. Additionally, CPL can image the PD via its red fluorescence. Finally, this platform can be metabolized out of the brain through cerebrospinal fluid circulation without causing obvious side effects, promising a robust treatment for PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Engineering vascularized tissues remains a promising approach for treating ischemic cardiovascular diseases. The availability of 3D-bioprinted vascular grafts that induce therapeutic angiogenesis can help avoid necrosis and excision of ischemic tissues. Here, using a combination of living cells and biodegradable hydrogels, we fabricated 3D-printed biocompatible proangiogenic patches from endothelial cell-laden photo-crosslinked gelatin (EC-PCG) bioink and smooth muscle cell-encapsulated polyurethane (SMC-PU) bioink. Implantation of 3D-bioprinted proangiogenic patches in a mouse model showed that EC-PCG served as an angiogenic capillary bed, whereas patterned SMC-PU increased the density of microvessels. Moreover, the assembled patterns between EC-PCG and SMC-PU induced the geometrically guided generation of microvessels with blood perfusion. In a rodent model of hindlimb ischemia, the vascular patches rescued blood flow to distal tissues, prevented toe/foot necrosis, promoted muscle remodeling, and increased the capillary density, thereby improving the heat-escape behavior of ischemic animals. Thus, our 3D-printed vascular cell-laden bioinks constitute efficient and scalable biomaterials that facilitate the engineering of vascular patches capable of directing therapeutic angiogenesis for treating ischemic vascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cancer stem cells (CSCs) characterized by self-renewal, invasiveness, tumorigenicity and resistance to treatment are regarded as the thorniest issues in refractory tumors. We develop a targeted and hierarchical controlled release nano-therapeutic platform (SEED-NPs) that self-identifies and responds to CSC and non-CSC micro-niches of tumors. In non-CSC micro-niche, reactive oxygen species (ROS) trigger the burst release of the chemotherapeutic drug and photosensitizer to kill tumor cells and reduce tumor volume by combining chemotherapy and photodynamic therapy (PDT). In CSC micro-niche, the preferentially released differentiation drug induces CSC differentiation and transforms CSCs into chemotherapy-sensitive cells. SEED-NPs exhibit an extraordinary capacity for downregulating the stemness of CD44 + /CD24 - SP (side population) cell population both in vitro and in vivo, and reveal a 4-fold increase of tumor-targeted accumulation. Also, PDT-generated ROS promote the formation of tunneling nanotubes and facilitate the divergent network transport of drugs in deep tumors. Moreover, ROS in turn promotes CSC differentiation and drug release. This positive-feedback-loop strategy enhances the elimination of refractory CSCs. As a result, SEED-NPs achieve excellent therapeutic effects in both 4T1 SP tumor-bearing mice and regular 4T1 tumor-bearing mice without obvious toxicities and eradicate half of mice tumors. SEED-NPs integrate differentiation, chemotherapy and PDT, which proved feasible and valuable, indicating that active targeting and hierarchical release are necessary to enhance antitumor efficacy. These findings provide promising prospects for overcoming barriers in the treatment of CSCs., Competing Interests: Declaration of competing interest All authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Local anesthetics are effective in relieving pain, but their duration of action is short. Therefore, the development of injectable sustained release systems to prolong the effect of local anesthetics has been of interest. In such systems delivering conventional local anesthetics, it has been challenging to achieve long durations of effect, particularly without incurring tissue toxicity. To overcome these challenges, we created a platform comprising a protein hydrogel incorporating hydrophobic local anesthetic (bupivacaine) nanoparticles. The nanoparticles were prepared by anti-solvent precipitation stabilized with bovine serum albumin (BSA), followed by crosslinking with glutaraldehyde (GA). The resulting BSA hydrogels prolonged release of bupivacaine in vitro. When bupivacaine nanoparticles within crosslinked BSA were injected at the sciatic nerve in rats, a duration of nerve block of 39.9 h was obtained, compared to 5.5 h for the commercial bupivacaine liposome suspension EXPAREL®. Tissue reaction was benign. We further demonstrated that this system could control the release of the amphiphilic drug diphenhydramine and the hydrophobic paclitaxel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Both ferroptotic therapy and immunotherapy have been widely employed in cancer treatment. However, ferroptotic cell death fails to induce dendritic cells maturation, which limits the therapeutic outcome of ferroptotic cancer therapy. To address this, the current work reports a tailored liposome to establish a positive loop between ferroptotic therapy and immunotherapy. As the key component of liposome, a unique phospholipid is designed to bear two arachidonic acid tails. The liposome is further surface-engineered with fucose ligand and physically encapsulates immunostimulatory CpG oligodeoxynucleotides (ODNs). The tailored liposome shows enhanced cellular uptake in a model 4T1 cell line. Meanwhile, the high level of reactive oxygen species in cancer cells can induce ferroptosis-specific peroxidation of DAPC and trigger the release CpG ODNs. The CpG ODNs further enable the maturation of dendritic cells and enhance the effector function of CD8 + T cells. IFN-γ released from CD8 + T cells promotes cancer cell ferroptosis via inhibiting SLC7A11 and suppressing the biosynthesis of glutathione. The tailored liposome can also act in synergism with PD-L1 antibody, resulting in enhanced anti-cancer efficacy in a 4T1 tumor-bearing mice model. This work provides a promising strategy for cancer treatment through orchestrating ferroptotic therapy and immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The tumor microenvironment (TME), which is mostly composed of tumor cells, immune cells, signaling molecules, stromal tissue, and the vascular system, is an integrated system that is conducive to the formation of tumors. TME heterogeneity makes the response to immunotherapy different in different tumors, such as "immune-cold" and "immune-hot" tumors. Tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are the major suppressive immune cells and their different phenotypes interact and influence cancer cells by secreting different signaling factors, thus playing a key role in the formation of the TME as well as in the initiation, growth, and metastasis of cancer cells. Nanotechnology development has facilitated overcoming the obstacles that limit the further development of conventional immunotherapy, such as toxic side effects and lack of targeting. In this review, we focus on the role of three major suppressive immune cells in the TME as well as in tumor development, clinical trials of different drugs targeting immune cells, and different attempts to combine drugs with nanomaterials. The aim is to reveal the relationship between immunotherapy, immunosuppressive TME and nanomedicine, thus laying the foundation for further development of immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Increasing evidence has showed that tumorigenesis is closely linked to inflammation, regulated by multiple signaling pathways. Among these, the cyclooxygenase-2/prostaglandin E 2 (COX-2/PGE 2 ) axis plays a crucial role in the progression of both inflammation and cancer. Inhibiting the activity of COX-2 can reduce PGE 2 secretion, thereby suppressing tumor growth. Therefore, COX-2 inhibitors are considered potential therapeutic agents for cancers. However, their clinical applications are greatly hindered by poor physicochemical properties and serious adverse effects. Fortunately, the advent of nanotechnology offers solutions to these limitations, enhancing drug delivery efficiency and mitigating adverse effects. Given the considerable progress in this area, it is timely to review emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and therapy. In this review, we first outline the various antineoplastic mechanisms of COX-2 inhibitors, then comprehensively summarize COX-2 inhibitors-based nanotherapeutics for cancer monotherapy, combination therapy, and diagnosis. Finally, we highlight and discuss future perspectives and challenges in the development of COX-2 inhibitors-based nanomedicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Liver fibrosis is featured by activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM). The Golgi apparatus in HSCs plays a vital role in synthesis and secretion of ECM proteins, while its targeted disruption in activated HSCs could be considered as a promising approach for liver fibrosis treatment. Here, we developed a multitask nanoparticle CREKA-CS-RA (CCR) to specifically target the Golgi apparatus of activated HSCs, based on CREKA (a specific ligand of fibronectin) and chondroitin sulfate (CS, a major ligand of CD44), in which retinoic acid (a Golgi apparatus-disturbing agent) chemically conjugated and vismodegib (a hedgehog inhibitor) encapsulated. Our results showed that CCR nanoparticles specifically targeted activated HSCs and preferentially accumulated in the Golgi apparatus. Systemic administration of CCR nanoparticles exhibited significantly accumulation in CCl 4 -induced fibrotic liver, which was attributed to specific recognition with fibronectin and CD44 on activated HSCs. CCR nanoparticles loaded with vismodegib not only disrupted Golgi apparatus structure and function but also inhibited the hedgehog signaling pathway, thus markedly suppressing HSC activation and ECM secretion in vitro and in vivo. Moreover, vismodegib-loaded CCR nanoparticles effectively inhibited the fibrogenic phenotype in CCl 4 -induced liver fibrosis mice without causing obvious toxicity. Collectively, these findings indicate that this multifunctional nanoparticle system can effectively deliver therapeutic agents to the Golgi apparatus of activated HSCs, thus has potential treatment of liver fibrosis with minimal side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Synthetic hydrogels are widely used as artificial 3D environments for cell culture, facilitating the controlled study of cell-environment interactions. However, most hydrogels are limited in their ability to represent the physical properties of biological tissues because stiffness and solute transport properties in hydrogels are closely correlated. Resultingly, experimental investigations of cell-environment interactions in hydrogels are confounded by simultaneous changes in multiple physical properties. Here, we overcame this limitation by simultaneously manipulating four structural parameters to synthesize a library of multi-arm poly (ethylene glycol) (PEG) hydrogel formulations with robustly decoupled stiffness and solute transport. This structural design approach avoids chemical alterations or additions to the network that might have unanticipated effects on encapsulated cells. An algorithm created to statistically evaluate stiffness-transport decoupling within the dataset identified 46 of the 73 synthesized formulations as robustly decoupled. We show that the swollen polymer network model accurately predicts 11 out of 12 structure-property relationships, suggesting that this approach to decoupling stiffness and solute transport in hydrogels is fundamentally validated and potentially broadly applicable. Furthermore, the unprecedented control of hydrogel network structure provided by multi-arm PEG hydrogels confirmed several fundamental modeling assumptions. This study enables nuanced hydrogel design for uncompromised investigation of cell-environment interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Inducing pyroptosis in cancer cells can result in a strong anti-tumor immune response. Our preliminary study indicates that pyroptosis can be temporarily strengthened by disrupting mitochondria, but ultimately diminished by defensive mitophagy. Here, this study reports a nano-system camouflaged with hybrid membranes consisting of homologous cell membrane and corresponding mitochondrial membrane, which is used to deliver a drug complex Ca@GOx consisting of calcium phosphate and glucose oxidase. By taking advantage of the homing effects of cell membrane and the orientated fusion mechanism of subcellular membrane, the nano-system is able to deliver Ca@GOx to mitochondria, induce mitochondrial Ca 2+ overload and generate significant levels of ROS, thus leading to pyroptosis. However, it's found that this system exhibits limited anti-tumor effects in vivo due to the compensatory activation of mitophagy serving as negative feedback to pyroptosis. To address this issue, mitophagy-inhibiting chloroquine is loaded into nanoparticles to intensify pyroptosis. As a result, the combination significantly promotes tumor infiltration of CD8 + T cells and improves anti-tumor effects. Together, this study establishes a rational combination of targeted mitochondria disruption and mitophagy blockage for effective pyroptosis-based therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Protein therapeutics have guided a transformation in disease treatment for various clinical conditions. They have been successful in numerous applications, but administration of protein therapeutics has been limited to parenteral routes which can decrease patient compliance as they are invasive and painful. In recent years, the synergistic relationship of novel biomaterials with modern protein therapeutics has been crucial in the treatment of diseases that were once thought of as incurable. This has guided the development of a variety of alternative administration routes, but the oral delivery of therapeutics remains one of the most desirable due to its ease of administration. This review addresses important aspects of micellar structures prepared by self-assembled processes with applications for oral delivery. These two characteristics have not been placed together in previous literature within the field. Therefore, we describe the barriers for delivery of protein therapeutics, and we concentrate in the oral/transmucosal pathway where drug carriers must overcome several chemical, physical, and biological barriers to achieve a successful therapeutic effect. We critically discuss recent research on biomaterials systems for delivering such therapeutics with an emphasis on self-assembled synthetic block copolymers. Polymerization methods and nanoparticle preparation techniques are similarly analyzed as well as relevant work in this area. Based on our own and others' research, we analyze the use of block copolymers as therapeutic carriers and their promise in treating a variety of diseases, with emphasis on self-assembled micelles for the next generation of oral protein therapeutic systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Gradient scaffolds are isotropic/anisotropic three-dimensional structures with gradual transitions in geometry, density, porosity, stiffness, etc., that mimic the biological extracellular matrix. The gradient structures in biological tissues play a major role in various functional and metabolic activities in the body. The designing of gradients in the scaffold can overcome the current challenges in the clinic compared to conventional scaffolds by exhibiting excellent penetration capacity for nutrients & cells, increased cellular adhesion, cell viability & differentiation, improved mechanical stability, and biocompatibility. In this review, the recent advancements in designing gradient scaffolds with desired biomimetic properties, and their implication in tissue regeneration applications have been briefly explained. Furthermore, the gradients in native tissues such as bone, cartilage, neuron, cardiovascular, skin and their specific utility in tissue regeneration have been discussed in detail. The insights from such advances using gradient-based scaffolds can widen the horizon for using gradient biomaterials in tissue regeneration applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The efficacy of standard glioblastoma (GBM) treatments has been limited due to the highly immunosuppressive tumor immune microenvironment, interpatient tumor heterogenicity and anatomical barriers, such as the blood brain barrier. In the present work, we hypothesized that a new local therapy based on the combination of doxorubicin (DOX) as an immunogenic cell death (ICD) inducer and CpG, a Toll-like receptor (TLR)-9 agonist, would act synergistically to eradicate GBM. DOX and CpG were first tested in an orthotopic GL261 GBM model showing enhanced survival. To improve the outcome with a reduced dose, we designed bioresponsive hyaluronic acid (HA)-drug conjugates for effective in situ chemoimmunotherapy. HA was derivatized with CpG. The new HA-CpG conjugate showed high efficacy in re-educating protumoral M2-like microglia into an antitumoral M1-like phenotype, inducing the expression of immune-stimulatory cytokines. DOX was also conjugated to HA. DOX conjugation increased ICD induction in GL261 cells. Finally, a combination of the conjugates was explored in an orthotopic GL261 GBM model. The local delivery of combined HA-DOX + HA-CpG into the tumor mass elicited antitumor CD8 + T cell responses in the brain tumor microenvironment and reduced the infiltration of M2-like tumor-associated macrophages and myeloid-derived suppressor cells. Importantly, the combination of HA-DOX and HA-CpG induced long-term survival in >66% of GBM-bearing animals than other treatments (no long-term survivor observed), demonstrating the benefits of conjugating synergistic drugs to HA nanocarrier. These results emphasize that HA-drug conjugates constitute an effective drug delivery platform for local chemoimmunotherapy against GBM and open new perspectives for the treatment of other brain cancers and brain metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: While lipid-lowering drugs have become a mainstay of clinical therapy these treatments only slow the progression of the disease and can have side effects. Thus, new treatment options are needed to supplement the effects of lipid lowering therapy for treating atherosclerosis. We examined the use of an inexpensive and widely available marine polysaccharide rhamnan sulfate as an oral therapeutic for limiting vascular inflammation and atherosclerosis., Methods and Results: We found rhamnan sulfate enhanced the barrier function of endothelial cells, preventing the deposition of LDL and maintaining barrier function even in the presence of glycocalyx-degrading enzymes. Rhamnan sulfate was also found to bind directly to FGF-2, PDGF-BB and NF-κB subunits with high affinity. In addition, rhamnan sulfate was a potent inhibitor of NF-κB pathway activation in endothelial cells by TNF-α. We treated ApoE -/- mice with a high fat diet for 4 weeks and then an addition 9 weeks of high fat diet with or without rhamnan sulfate. Rhamnan sulfate reduced vascular inflammation and atherosclerosis in both sexes of ApoE -/- mice but had a stronger therapeutic effect in female mice. Oral consumption of rhamnan sulfate induced a significant decrease in cholesterol plasma levels in female mice but not in male mice. In addition, there was a marked reduction in inflammation for female mice in the liver and aortic root in comparison to male mice., Conclusions: Rhamnan sulfate has beneficial effects in reducing inflammation, binding growth factors and NF-κB, enhancing endothelial barrier function and reducing atherosclerotic plaque formation in ApoE -/- mice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Aaron Baker reports financial support was provided by National Institutes of Health. Aaron Baker reports financial support was provided by US Office of Congressionally Directed Medical Research Programs. Aaron Baker reports financial support was provided by American Heart Association. Robert Linhardt reports financial support was provided by National Institutes of Health., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The efficacy of radiotherapy is greatly challenged by intense hypoxia, intricate stroma and suppressive immune microenvironments in tumors. Herein, we rationally designed a microvesicle-inspired oxygen-delivering polyfluorocarbon nanosystem loading DiIC18(5) and halofuginone (M-FDH) with prominent capacity of improving tumor oxygenation and intratumor distribution, synergizing radiation to disrupt tumor stroma and boost antitumor immunity for combinational cancer therapy. M-FDH produced a 10.98-fold enhancement of tumor oxygenation and caused efficient production of reactive oxygen species (ROS) upon radiation. M-FDH + X ray treatment resulted in notable DNA damages, over 90% elimination of cancer-associated fibroblasts (CAFs) and major components of extracellular matrix, significant enhancement of tumoricidal CD3 + CD8 + T cells, and profound elimination of suppressive immune cells in 4T1 tumors. The therapeutic benefits of M-FDH + X ray on suppressing tumor growth were confirmed in two murine tumor models. Therefore, this study provides an encouraging microvesicle-inspired strategy to target cancer cells and CAFs in tumors and synergize radiotherapy for effective cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Diabetes immunity-modulated wound treatment in response to the varied microenvironments at different stages remains an urgent challenge. Herein, glucose oxidase (GOx) and quasi-amorphous Fe 2 O 3 are co-incorporated into Zn-MOF nanoparticle (F-GZ) for cascade enzyme catalytic activities, where not only the high blood glucose in the wound is consumed via the GOx catalysis, but also the effective anti-bacteria is achieved via the degradedly released Zn 2+ synergistically with the catalytically produced ·OH during the bacterial infection period with the low pH microenvironment. Simultaneously, the reactive oxygen species scavenging and hypoxia relief is realized via catalyzing H 2 O 2 to produce O 2 at the relatively elevated pH environment during the wound recovery period. Subsequently, a multifunctional hydrogel with injectable, self-healing and hemostasis abilities, as well as uniformed F-GZ loading is prepared via the copolymerization reaction. This hydrogel behaves as F-GZ but reduces the toxic effects, which thus accelerates the diabetic wound healing. More importantly, this hydrogel is found to modulate the diabetes immunity possibly mediated via the released Zn 2+ , which thus contributes to the recovered pancreatic islet functions with improved glucose tolerance and increased insulin secretion for enhanced diabetic wound treatments. This work initiates a new strategy for simultaneous diabetic wound management and also suggests a potential way for diabetic immunity modulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control. Hence, we design and construct an aptamer-decorated hypoxia-responsive nanoparticle s(DGL) n @Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart codelivery strategy provides an inspiring opportunity in PDAC treatment., (Copyright © 2022. Published by Elsevier Ltd.)

Intratumoral environment as a hypoxic, non-inflamed "cold" state is difficult for many agents to accumulate and activate the immune system. Intrinsically, facultative anaerobic Salmonella VNP20009 target the tumor hypoxic areas, invade into tumor cells and exhibit an immune effect. Here we engineer the bacteria by decorating their surface with newly synthesized heptamethine cyanine dyes NHS-N782 and JQ-1 derivatives to obtain the biohybrid agent N-V-J, leading to the deep tumor targeted photothermal therapy and magnified immunotherapy. Due to the mitochondrial targeting capacity of NHS-N782, N-V-J becomes susceptive to the temperature rise when reaching tumors. This synergistic strategy promotes the systemic immunity by creating an inflamed "hot" tumor state from three different dimensions, which include the inherent immunogenicity of bacteria, the near-infrared laser triggered tumor antigens and the downregulation of PD-L1 expression. All these approaches result in effective and long-lasting T cell immune responses to prevent local and distant tumors for extended time. Leveraging the attenuated bacteria to transport dual drugs to the tumor tissues for self-synthetic vaccines provides a novel paradigm to enhance the bacteria-mediated cancer immunotherapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Lung cancer is a major contributor to cancer-related death worldwide. siRNA nanomedicines are powerful tools for cancer therapeutics. However, there are challenges to overcome to increase siRNA delivery to solid tumors, including penetration of nanoparticles into a complex microenvironment following systemic delivery while avoiding rapid clearance by the reticuloendothelial system, and limited siRNA release from endosomes once inside the cell. Here we characterized cell uptake, intracellular trafficking, and gene silencing activity of miktoarm star polymer (PDMAEMA-POEGMA) nanoparticles (star nanoparticles) complexed to siRNA in lung cancer cells. We investigated the potential of nebulized star-siRNA nanoparticles to accumulate into orthotopic mouse lung tumors to inhibit expression of two genes [βIII-tubulin, Polo-Like Kinase 1 (PLK1)] which: 1) are upregulated in lung cancer cells; 2) promote tumor growth; and 3) are difficult to inhibit using chemical drugs. Star-siRNA nanoparticles internalized into lung cancer cells and escaped the endo-lysosomal pathway to inhibit target gene expression in lung cancer cells in vitro. Nebulized star-siRNA nanoparticles accumulated into lungs and silenced the expression of βIII-tubulin and PLK1 in mouse lung tumors, delaying aggressive tumor growth. These results demonstrate a proof-of-concept for aerosol delivery of star-siRNA nanoparticles as a novel therapeutic strategy to inhibit lung tumor growth., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immune regulation therapies have been considered promising in the treatment of myocardial ischemia reperfusion (MI/R) injury. Mesenchymal stem cells derived extracellular vesicles (MSC-EVs) are of great potential for immune modulation by reprogramming macrophages but their therapeutic efficacy is hindered by insufficient targeting ability in vivo. Herein, we introduced the platelet membrane modified EVs (P-EVs) based on membrane fusion method to mimic the binding ability of platelets to monocytes. In the mouse model of MI/R injury, the intravenously injected P-EVs were mainly carried by circulating monocytes into the ischemic myocardium. In the inflammatory microenvironment, those monocytes subsequently differentiated into macrophages with enhanced phagocytosis, which probably promoted in-situ endocytosis of the superficial P-EVs by monocytes differentiated macrophages in large quantities. Then, the P-EVs successfully escaped from the macrophage lysosome and released the functional microRNAs (miRNAs) into the cytosol which facilitated the inflammatory macrophages (M1 phenotype) reprogramming to reparative macrophages (M2 phenotype). Finally, the immune microenvironment was regulated to realize cardiac repair. Thus, we supposed that the most likely delivery method was that monocytes mediated P-EVs migration into ischemic myocardium where P-EVs were mainly in-situ endocytosed by monocytes derived macrophages, which holds potential for immunoregulation on MI/R and other immune-related diseases in the future., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Retinoblastoma is the most common primary intraocular malignancy in infancy with a metastases-related death risk. However, a safe and convenient treatment without enucleation is still an unmet clinical need. In this work, a cell-penetrating peptide, 89WP, was conjugated with melphalan (89WP-Mel), which achieved high tumor inhibition effects as intravitreally injected melphalan via topical instillation for the first time. Notably, the "outside-in" diffusion of instilled 89WP-Mel created a protective shield surrounding the eye, efficiently preventing tumor metastases, while the mice treated with intravitreally injected melphalan suffered more brain metastases related death. The ocular absorption of 89WP-conjugated melphalan and other small molecules, both hydrophobic and hydrophilic, occurred via non-corneal pathway with high safety and a prolonged residence duration in retina up to 24 h. The present work paves a new avenue for simultaneous intraocular tumor inhibition and extraocular metastases prevention in a safe and convenient way via topical instillation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Colon cancer is emerging as one of the most prevalent cancers globally. Oral colonic drug delivery systems have attracted considerable attention in the treatment of orthotopic colon cancer due to their superior properties. However, the particularity and complexity of the gastrointestinal structure are a hindrance to the safe delivery of drugs to the target site of the colon tumor. Herein, to achieve an effective delivery system specifically targeting the colon, we designed paclitaxel (PTX)-loaded oral colon double-targeted nanoparticles using polylactic acid-polyethyleneimine (PLA-PEI) and hyaluronic acid-inulin (HA-IN). IN is enzyme sensitive and hardly degraded in the upper digestive tract; as such, it can ensure the safe delivery of nanoparticles to the colon. The "IN shell" is degraded by colon-specific bacteria at the colon site. The exposed HA not only promotes intestinal mucosal crossing of nanoparticles, but also acts as the target of CD44 and plays an active targeting role in tumor tissues. The action of the proton sponge effect of PEI induces the successful release of the nanoparticle. The prepared nanoparticles have a negative charge of -19.5 ± 1.2 mV and a size of 176.7 ± 0.3 nm with a narrow PDI of 0.148 ± 0.004. C26 cells were used for in vitro anticancer studies, including fluorescence staining and flow cytometry, and to explore inhibition of proliferation. The analysis demonstrated that the nanoparticles were more efficiently taken up by cancer cells, exhibiting greater cytotoxicity and apoptosis-inducing ability compared to free drugs. Moreover, in vivo studies revealed that the nanoparticles could remain in vivo for 24 h and accumulate at the tumor site. These data provide evidence of the therapeutic effect on orthotopic colon cancer. Also, safety evaluation results demonstrated that PLA-PEI/HA-IN is a safe drug delivery vector, therefore, holds great promise as a new therapeutic strategy for orthotopic colon cancer treatment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The biomaterial-based immunoengineering has become one of the most attractive research fields in the last decade. In the present study, a solid-in-oil-in-water (S/O/W) emulsion encapsulating antigen in the oil phase of an oil-in-water (O/W) emulsion was prepared as a novel vaccine carrier consisting of similar materials to the emulsion adjuvant of which the safety, immunogenicity and vaccination efficacy have been already confirmed in human. Direct observation by high-resolution confocal laser scanning microscopy and small angle X-ray scattering analysis showed that the antigens were dispersed inside of the oil phase of the S/O/W emulsion as solid-state particles. The S/O/W emulsion robustly produced antigen-specific antibodies and enhanced the antitumor effects in a therapeutic cancer vaccination compared with free antigens or the O/W emulsion in vivo. This result is in good agreement with the activation effect of antigen-specific cytotoxic T lymphocytes and antigen presentation by the S/O/W emulsion, indicating that the S/O/W emulsion consisting of already approved materials is a promising vaccine carrier to produce both humoral and cellular immunity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intervention of the over-activated microglia-aggravated neuroinflammation represents a promising therapeutic strategy for Alzheimer's disease (AD). Upregulation of triggering receptor expressed on myeloid cells-2 (TREM2) attenuates the neuroinflammatory processes and normalizes the dysfunctional microglia. However, Trem2-gene therapy for AD by the effective non-invasive delivery systems is unexploited. Herein, we report the microglia-targeted gene delivery systems (PHSA@PF/pTREM2) composed of a core of fluorinated polyethylenimine condensing the TREM2-encoding plasmid (PF/pTREM2) and a shell of human serum albumin conjugated with both cis-aconitic anhydride and neural cell adhesion molecule-mimetic peptide P2 (PHSA). Thanks to the shedding effect of the albumin coated, PHSA@PF/pTREM2 exhibit prolonged blood circulation and low cytotoxicity. PHSA@PF/pTREM2 achieve brain accumulation as high as 2.17% injected dose per gram of brain and the microglial-targeting effect (targeting specificity of 41.9%) via the systemic administration. The nanocomplexes can be detached PHSA-shell in the acidic endo-lysosomes via the cleavage of cis-aconitic amide bond, resulting in PF/pTREM2 exposure for efficient endo-lysosomal escape and gene transfection. PHSA@PF/pTREM2 upregulate the TREM2 level and regulate microglial polarization toward M2-phenotype for remodeling the inflammatory microenvironment and enhanced Aβ clearance, leading to an improvement of cognitive performance in APP/PS1 mice. This work provides a promising gene delivery platform to reverse dysfunctional microglia for AD therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Despite tremendous progress achieved in immunotherapy, many critical challenges in treating pancreatic ductal adenocarcinoma (PDAC) persist. Considering the poor vascularization of PDAC, after intramuscular administration exosomes can targeted deliver "cargos" to pancreatic tumors and bypass obstructions of the intrinsic overexpressed stroma through lymphatics. Herein, we propose a strategy to derive exosomes from immunogenically dying tumor cells and exploit their properties for several purposes, including antigen presentation, adjuvant supply, and "cargo" delivery of vaccines against pancreatic cancer via intramuscular injection. To enhance the immunostimulatory effects, the MART-1 peptide is modified to the exosomes to expand T-cell-related responses. Furthermore, CCL22 siRNA is electroporated into the exosomes (referred to as spMEXO) to hinder the CCR4/CCL22 axis between DCs and Tregs, thereby suppressing Treg expansion. Both in vitro and in vivo studies demonstrate that spMEXO can serve as an effective prophylactic vaccine to delay tumor growth, whereas combining spMEXO with PDAC first-line chemotherapeutics (co-administration of gemcitabine with albumin-paclitaxel) demonstrated significantly enhanced therapeutic effects in established PANC-02 tumors. Therefore, the present work provides an effective strategy to employ cancer vaccines through intramuscular injection in PDAC and highlights the potential of exosomes derived from immunogenically dying tumor cells as a versatile tool to develop nanovaccines for immunotherapy., (Copyright © 2021. Published by Elsevier Ltd.)

The in vivo fate of nanoformulated drugs is governed by the physicochemical properties of the drug and the functionality of nanocarriers. Nanoformulations such as polymeric micelles, which physically encapsulate poorly soluble drugs, release their payload into the bloodstream during systemic circulation. This results in three distinct fractions of the drug-nanomedicine: encapsulated, protein-bound, and free drug. Having a thorough understanding of the pharmacokinetic (PK) profiles of each fraction is essential to elucidate mechanisms of nanomedicine-driven changes in drug exposure and PK/PD relationships pharmacodynamic activity. Here, we present a comprehensive preclinical assessment of the poly (2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PM), including bioequivalence comparison to the clinically approved paclitaxel nanomedicine, Abraxane®. Physicochemical characterization and toxicity analysis of POXOL hl-PM was conducted using standardized protocols by the Nanotechnology Characterization Laboratory (NCL). The bioequivalence of POXOL hl-PM to Abraxane® was evaluated in rats and rhesus macaques using the NCL's established stable isotope tracer ultrafiltration assay (SITUA) to delineate the plasma PK of each PTX fraction. The SITUA study revealed that POXOL hl-PM and Abraxane® had comparable PK profiles not only for total PTX but also for the distinct drug fractions, suggesting bioequivalence in given animal models. The comprehensive preclinical evaluation of POXOL hl-PM in this study showcases a series of widely applicable standardized studies by NCL for assessing nanoformulations prior to clinical investigation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ischemic stroke leads to high disability and mortality. The limited delivery efficiency of most therapeutic substances is a major challenge for effective treatment of ischemic stroke. Inspired by the prominent merit of nanoscale particles in brain targeting and blood-brain barrier (BBB) penetration, various functional nanoparticles have been designed as promising drug delivery platforms that are expected to improve the therapeutic effect of ischemic stroke. Based on the complex pathological mechanisms of ischemic stroke, this review outline and summarize the rationally designed nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke, including recanalization therapy, neuroprotection therapy, and combination therapy. On this bases, the potentials and challenges of nanoparticles in the treatment of ischemic stroke are revealed, and new thoughts and perspectives are proposed for the design of feasible nanoparticles for effective treatment of ischemic stroke., (Copyright © 2021 Elsevier Ltd. All rights reserved.)