Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.

Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.

While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.

Aortic Angiosarcoma Manifesting as Multiple Musculoskeletal Metastases: A Case Report.

Aortic angiosarcomas are rare. Due to its rarity and metastatic presentation, it is difficult to diagnose metastatic aortic angiosarcoma. We describe the clinicopathological and radiologic features of a metastatic aortic angiosarcoma presenting as musculoskeletal metastases. A 59-year-old male patient presented with left thigh pain. Plain radiographs revealed multifocal osteolytic lesions in the left femur shaft. Abdominopelvic computed tomography showed a lobulated osteolytic lesion in the left iliac bone. Magnetic resonance images revealed multifocal soft tissue lesions in the thigh musculature. A positron emission tomography/computed tomography (PET/CT) scan demonstrated multiple foci of increased uptake in the left femur bone, pelvis, left thigh, and calf musculature. Focal increased uptake in the lower abdominal aorta was newly detected. Pelvis biopsy showed tumor cell nests of epithelioid cells. The tumor cells showed vasoformative features. Immunohistochemically, the tumor cells showed positivity for vimentin, CD31, and ERG. The pathologic diagnosis of epithelioid angiosarcoma was established. The origin of the tumor was presumed to be the aorta. This case underscores the importance of PET scans in identifying primary lesions. In terms of the histopathologic diagnosis of biopsy samples with tumor cells exhibiting epithelioid neoplastic morphology, employing appropriate ancillary techniques such as immunocytochemistry with vascular markers may assist in accurately diagnosing metastatic angiosarcoma.

Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Self-Assembled Tamoxifen-Selective Fluorescent Nanomaterials Driven by Molecular Structural Similarity.

Most supramolecular systems were discovered by using a trial-and-error approach, leading to numerous synthetic efforts to obtain optimal supramolecular building blocks for selective guest encapsulation. Here, we report a simple coassembly strategy for preparing tamoxifen-selective supramolecular nanomaterials in an aqueous solution. The synthetic amphiphile molecule, 1,1,2,2-tetraphenylethylene (TPE), promotes large tamoxifen aggregate disassembly into smaller, discrete aggregates such as ribbon-like and micellar assemblies in coassembled solutions, enhancing the solubility and dispersion. The TPE moiety exhibits enhanced emission upon tamoxifen interaction, enabling the observation of the coassembled species in an aqueous solution for cell imaging. The tamoxifen-selective fluorescent micelles in the presence of a 1:1 molar ratio of TPE derivative with tamoxifen show enhanced tamoxifen absorption and anticancer effects against MCF-7 breast cancer cells. These supramolecular approaches, based on the coassembly of building blocks with molecular structural similarity, can provide a novel strategy for the efficient development of selective molecular carriers with enhanced biological activities.

Modulating the folding and binding of peptides using a stimuli-responsive molecular tweezer.

This study presents the development of a ß-hairpin (tryptophan zipper, Trpzip)-based molecular tweezer (MT) that can control the folding and binding of α-helical peptides. When an α-helix isolated from the p53 protein was conjugated with Trpzip in an optimized macrocyclic structure, the folded ß-hairpin stabilized the helix conformation through the side chain-to-side chain stapling strategy, which notably enhanced target (hDM2) affinity of the peptide. On the other hand, the helicity and binding affinity were significantly reduced when the hairpin was unfolded by a redox stimulus. This stimulus-responsive property was translated into the effective capture and release of model multivalent biomaterials, hDM2-gold nanoparticle conjugates. Since numerous protein interactions are mediated by α-helical peptides, these results suggest that the ß-hairpin-based MT holds great potential to be utilized in various biomedical applications, such as protein interaction inhibition and cancer biomarker (e.g., circulating tumor cells and exosomes) detection.

Peptide Assembly of Different Dimensions and Their Effect on Myoblast Proliferation.

Variations in the functionalities of materials of different dimensions containing the same functional groups can be attributed to the structural stability and morphology of the materials. The morphology of peptide assemblies can influence their interactions with biological systems and ultimately modulate their bioactivity. Among reported Arg-Gly-Asp (RGD)-based supramolecular materials, two-dimensional (2-D) peptide assembly has been rarely studied. Herein, we report the fabrication of RGD-based supramolecular one-dimensional (1-D) and 2-D assemblies as peptide-based myoblast growth accelerators. The 2-D assembly was more effective in proliferating C2C12 cells than the 1-D assembly. These findings provide insights into the construction of optimal RGD-based supramolecular functional materials of different dimensions.

Effects of exogenous protease on performance, economic evaluation, nutrient digestibility, fecal score, intestinal morphology, blood profile, carcass trait, and meat quality in broilers fed normal diets and diets considered with matrix value.

This study was conducted to estimate the effects of exogenous protease on performance, economic evaluation, nutrient digestibility, fecal score, intestinal morphology, blood profile, carcass traits, and meat quality in broilers fed normal diets and diets considered with matrix value. A total of 90, one-day-old Arbor Acres broiler chickens were randomly allocated to 3 dietary treatments with 6 replicates and each replicate of 5 broiler chickens. Treatments were as follows: 1) Basal diet (positive control, PC), 2) Basal diet formulated with full ProAct 360 matrix at 50 g/MT without addition of ProAct 360 (negative control, NC), 3) NC + 50 g/MT ProAct 360 (PA). Supplementation of exogenous protease to nutrient deficient NC diet by matrix values (PA) tended to increase growth performance and significantly improved intestinal morphology compared with the NC group. The PA group had significantly lower fecal score, and higher ATTD of crude protein and amino acids than those of the NC group. Furthermore, supplementation of exogenous protease to NC diet decreased feed cost, resulting in improved profit margin. However, there was no significant difference on carcass yield and relative organ weight. In conclusion, supplementation of exogenous protease using matrix value could be used as economic additive to improve growth, profit margin, digestibility, and gut health in broiler chickens.

Effects of supplemental different clay minerals in broiler chickens under cyclic heat stress.

The objective of this study was to investigate the effect of supplementing clay minerals and organic chromium in feed on broiler chicken under heat stress (HS). A total of 90 one-day-old broiler chicken (Arbor Acres) with an initial body weight of 45.0 ± 0.2 g were assigned to five treatment groups (six replications, three birds each cage): 1) NC group, basal diet under room temperature environment; 2) PC group, basal diet under high temperature (HT) environment; 3) ILT group, basal diet + 1% illite + HT; 4) ZLT group, basal diet + 1% zeolite + HT; 5) OC group, basal diet + 400 ppb/kg organic chromium + HT. The ILT and ZLT groups had significantly higher body weight than the PC group in 4 weeks. Apparent total tract digestibility of gross energy was increased in the ILT, ZLT, and OC groups compared to the PC group. The NC group had lower foot-pad dermatitis score than other groups. Escherichia coli population in the cecum and feces was decreased in the ZLT group than in the PC group. Lactobacillus in cecum and feces was significantly increased in the ZLT group than in the PC group. Regarding blood profiles, blood cortisol was decreased in the NC and ILT groups compared to the PC group. Water holding capacity and pH were increased in the ZLT group than the PC group. In conclusion, according to the results of growth performance, nutrients digestibility, bacteria counts, and meat characteristics, supplementation of the ZLT in broiler diet can alleviate HS.

Reduction-Responsive Supramolecular Sheets for Selective Regulation of Facultative Anaerobe Agglutination.

Stimuli-responsive supramolecular materials have promising biological applications because of their ability to rapidly undergo significant structural changes in response to diverse stimuli. Herein, supramolecular sheets assembled via charge-transfer interactions between the pyrene moiety of a d-mannose-containing amphiphile and 7,7,8,8-tetracyanoquinodimethane (TCNQ) are reported. The supramolecular sheets show reduction-responsive behavior, in which their disassembly is triggered by the reduction of TCNQ by sodium sulfide. In an anaerobic environment, the sheet structure remains intact and the exposed d-mannose moieties induce the agglutination of facultative anaerobes, thereby inhibiting bacterial growth. In contrast, in an aerobic environment, the reduction of TCNQ by the hydrogen sulfide generated by facultative anaerobes causes sheet disassembly. This enables continuous bacterial growth, because the collapsed sheets cannot induce agglutination. Thus, this study presents a novel supramolecular material for the selective regulation of facultative anaerobe growth according to the external environment.

Two-Dimensional Peptide Assembly via Arene-Perfluoroarene Interactions for Proliferation and Differentiation of Myoblasts.

Supramolecular assembly based on aromatic interactions can provide well-defined nanostructures with an understanding of intermolecular interactions at the molecular level. The peptide assembly via a supramolecular approach can overcome the inherent limitations of bioactive peptides, such as proteolytic degradations and rapid internalizations into the cytosol. Although extensive research has been carried out on supramolecular peptide materials with a two-dimensional (2D) structure, more needs to be reported on biological activity studies using well-defined 2D peptide materials. Physical and chemical properties of the 2D peptide assembly attributed to their large surface area and flexibility can show low cytotoxicity, enhanced molecular loading, and higher bioconjugation efficiency in biological applications. Here, we report supramolecular 2D materials based on the pyrene-grafted amphiphilic peptide, which contains a peptide sequence (Asp-Gly-Glu-Ala; DGEA) that is reported to bind to the integrin α2ß1 receptor in 2D cell membranes. The addition of octafluoronaphthalene (OFN) to the pyrene-grafted peptide could induce a well-ordered 2D assembly by face-centered arene-perfluoroarene stacking. The DGEA-peptide 2D assembly with a flat structure, structural stability against enzymatic degradations, and a larger size can enhance the proliferation and differentiation of muscle cells via continuous interactions with cell membrane receptors integrin α2ß1 showing a low intracellular uptake (15%) compared to that (62%) of the vesicular peptide assembly. These supramolecular approaches via the arene-perfluoroarene interaction provide a strategy to fabricate well-defined 2D peptide materials with an understanding of assembly at the molecular level for the next-generation peptide materials.

Effect of loading density and weather conditions on animal welfare and meat quality of slaughter pigs.

There are several factors that affect the welfare and meat quality of pigs during pre-slaughter transport. Among various factors, the effects of weather conditions and loading density were studied. A total of 3,726 finishing pigs were allotted to one of nine groups arranged in a 3 × 3 factorial design according to the weather conditions (low temperature [LT], under 10°C; normal temperature [NT], 10°C-24°C; high temperature [HT], upper 24°C), and loading density (low density [LD], upper 0.43 m2/100 kg; normal density [ND], 0.37-0.43 m2/100 kg; high density [HD], under 0.37 m2/100 kg). Each treatment group follow as: LTLD, LTND, LTHD, NTLD, NTND, NTHD, HTLD, HTND, HTHD. In terms of carcass composition, pigs had the highest carcass weight and backfat thickness at LT. Comparing the HD transport to the ND transport, the meat quality indicated a lower pH and more drip loss. The incidence rate of pale, soft, exudative (PSE) pork was high in the order of the HD, LD, and the ND transport (20%, 9%, and 2%, respectively). The HT transport showed the lowest pH and greatest L* value under the given weather conditions. Pigs transported under the HTHD and LTLD conditions had the greatest rates of PSE pork (40% and 20%, respectively). Pigs exposed to HD transport had the shortest laying time and the highest overplap behavior. The LDLT transport pigs had a shorter laying time than the LDNT and LDHT transport pigs. In conclusion, too high or too low density transport is generally not excellent for meat quality or animal welfare, however it is preferable to transport at a slightly low density at high temperature and at a slightly high density at low temperature.

Photoswitchable Microgels for Dynamic Macrophage Modulation.

Dynamic manipulation of supramolecular self-assembled structures is achieved irreversibly or under non-physiological conditions, thereby limiting their biomedical, environmental, and catalysis applicability. In this study, microgels composed of azobenzene derivatives stacked via π-cation and π-π interactions are developed that are electrostatically stabilized with Arg-Gly-Asp (RGD)-bearing anionic polymers. Lateral swelling of RGD-bearing microgels occurs via cis-azobenzene formation mediated by near-infrared-light-upconverted ultraviolet light, which disrupts intermolecular interactions on the visible-light-absorbing upconversion-nanoparticle-coated materials. Real-time imaging and molecular dynamics simulations demonstrate the deswelling of RGD-bearing microgels via visible-light-mediated trans-azobenzene formation. Near-infrared light can induce in situ swelling of RGD-bearing microgels to increase RGD availability and trigger release of loaded interleukin-4, which facilitates the adhesion structure assembly linked with pro-regenerative polarization of host macrophages. In contrast, visible light can induce deswelling of RGD-bearing microgels to decrease RGD availability that suppresses macrophage adhesion that yields pro-inflammatory polarization. These microgels exhibit high stability and non-toxicity. Versatile use of ligands and protein delivery can offer cytocompatible and photoswitchable manipulability of diverse host cells.

Tumor-Specific Monomethyl Auristatin E (MMAE) Prodrug Nanoparticles for Safe and Effective Chemotherapy.

A prodrug is bioreversible medication that is specifically converted to the active drugs by enzymes overexpressed in the tumor microenvironment, which can considerably reduce the chemotherapy-induced side effects. However, prodrug strategies usually have low antitumor efficacy compared to free drugs by delayed drug release. This is because they need time to be activated by enzymatic cleavage and they also cannot be fully recovered to the active drugs. Therefore, highly potent anticancer drug should be considered to expect a sufficient antitumor efficacy. Herein, we propose tumor-specific monomethyl auristatin E (MMAE) prodrug nanoparticles for safe and effective chemotherapy. The cathepsin B-specific cleavable FRRG peptide and MMAE are chemically conjugated via one-step simple synthetic chemistry. The resulting FRRG-MMAE molecules form stable nanoparticles without any additional carrier materials by hydrophobic interaction-derived aggregations. The FRRG-MMAE nanoparticles efficiently accumulate within the tumor tissues owing to the enhanced permeability and retention (EPR) effect and inhibit the tubulin polymerization by releasing free MMAE in the cathepsin B-overexpressed tumor cells. In contrast, FRRG-MMAE nanoparticles maintain a non-toxic inactive state in the normal tissues owing to innately low cathepsin B expression, thereby reducing MMAE-related severe toxicity. Collectively, this study provides a promising approach for safe and effective chemotherapy via MMAE-based prodrug nanoparticles, which may open new avenues for advanced drug design for translational nanomedicine.

Transformation of Supramolecular Membranes to Vesicles Driven by Spontaneous Gradual Deprotonation on Membrane Surfaces.

The various proteins and asymmetric lipid bilayers present in cell membranes form curvatures, resulting in structural transformations to generate vesicles. Fission and fusion processes between vesicles and cell membranes are reversible in living organisms. Although the transformation of a two-dimensional membrane to a three-dimensional vesicle structure is a common natural phenomenon, the lack of a detailed understanding at the molecular level limits the development of synthetic systems for functional materials. Herein, we report a supramolecular membrane system through donor-acceptor interactions using a π-deficient acceptor and π-rich donor as building blocks. The reduced electrostatic repulsion between ammonium cations and the spontaneously deprotonated neutral amino group induced anisotropic membrane curvature, resulting in membrane fission to form vesicles with a detailed understanding at the molecular level. Furthermore, the reversible transformation of vesicles to membranes upon changing the pH provides a novel synthetic system exhibiting both fission and fusion processes.

Comparative study of cathepsin B-cleavable linkers for the optimal design of cathepsin B-specific doxorubicin prodrug nanoparticles for targeted cancer therapy.

A carrier-free prodrug nanoparticle has emerged as a potential approach to cancer therapy. It plays a vital role in enhancing the tumor targeting and therapeutic efficacy of the anticancer agent at sites of intention wherein the prodrug nanoparticle is potentially activated. Herein, five derivatives of cathepsin B-cleavable prodrugs are synthesized via chemically conjugating different cathepsin B-cleavable peptides (Phe-Arg-Arg-Gly, Phe-Arg-Arg-Leu, Phe-Arg-Arg-Leu-Gly, Phe-Leu-Arg-Arg-Gly) to doxorubicin (DOX). The peptide-DOX prodrugs can spontaneously assemble into nanoparticles via their intermolecular hydrophobic and π-π stacking interactions. The resulting cathepsin B-cleavable prodrugs nanoparticles formed different nanoparticle structures according to the amphiphilicity and flexibility of different peptides and their particle stability and cellular uptake mechanism are carefully evaluated in vitro. Among five prodrug nanoparticles, the Phe-Arg-Arg-Leu-DOX (FRRL-DOX) nanoparticle was formed to a size of 167.5 ± 12.4 nm and stably maintains its nanoparticle structure in saline media for 3 days. The FRRL-DOX nanoparticle is well taken up by tumoral nuclei and effectively induces cancer cell death with minimal toxicity to normal cells. In addition, the FRRL-DOX nanoparticle shows 2.3-16.3-fold greater tumor-specific accumulation in vivo than other prodrug nanoparticles and free DOX. The therapeutic effect of FRRL-DOX is finally examined, demonstrating 2.1-fold better anticancer efficacy compared to that of free DOX. Notably, the FRRL-DOX nanoparticle does not exert serious toxicity in its repeated intravenous administration at a high dose of up to 10 mg/kg (equiv. to DOX). In conclusion, the peptide sequence for cathepsin B-cleavable prodrug nanoparticle is determined to be successfully optimized in a way of increasing its tumor selectivity and lowering toxicity to normal tissues.

Recognition of 3D Chiral Microenvironments for Myoblast Differentiation.

Cell chirality plays a critical role in the linkage between molecular chirality and the asymmetrical biological functions of body organs. However, enantioselective interactions between cell chirality and the extracellular environment are not yet fully understood. In this study, we investigated the effects of structurally chiral extracellular microenvironments on cellular alignments and differentiations. Twisted wrinkle-shaped chiral micropatterns were prepared using biaxial and asymmetric buckling methods, wherein structural handedness was determined from the orientation of the tilt angle between the first and second microwrinkles. Myoblasts were separately cultured on two enantiomeric chiral micropatterns in a mirror-reflected shape. Cells cultured on the left-handed chiral micropatterns preferred alignments along the direction of the second microwrinkle, with a relatively deeper valley than that of the first microwrinkle. The aligned cells on the left-handed pattern showed higher differentiation rates, as assessed by fusion indices and marker protein expression levels, than those cultured on right-handed chiral micropatterns. These results suggest that myoblasts exhibit enantioselective recognition of structurally chiral microenvironments, which can promote cellular alignments and differentiation.

Stimbiotic Supplementation Alleviates Poor Performance and Gut Integrity in Weaned Piglets Induced by Challenge with E. coli.

The aim of this study was to investigate the effects of stimbiotic (STB), a xylanase and xylo-oligosaccharide complex. A total of 36 male weaned pigs with initial body weights of 8.49 ± 0.10 kg were used in a 3-week experiment. The experiment was conducted in a 2 × 3 factorial arrangement (six replicates/treatment) of treatments consisting of two levels of challenge (challenge and non-challenge) and three levels of STB (0, 0.5, and 1 g/kg diet). Supplementations STB 0.5 g/kg (STB5) and STB 1 g/kg (STB10) improved the G:F (p = 0.04) in piglets challenged with STEC. STB supplementation, which also decreased (p < 0.05) the white blood cells, neutrophils, lymphocytes, and expression levels of tumor necrosis factor-alpha and interleukin-6. Supplementations STB5 and STB10 improved (p < 0.01) the lymphocytes and neutrophils in piglets challenged with STEC on 14 dpi. Additionally, supplementations STB5 and STB10 improved (p < 0.01) the tumor necrosis factor-alpha in piglets challenged with STEC on 3 dpi. Supplementations STB5 and STB10 also improved the villus height-to-crypt depth ratio (p < 0.01) in piglets challenged with STEC. Supplementation with STB reduced (p < 0.05) the expression levels of calprotectin. In conclusion, STB could alleviate a decrease of the performance, immune response, and inflammatory response induced by the STEC challenge.

Selective Anticancer Materials by Self-Assembly of Synthetic Amphiphiles Based on N-Acetylneuraminic Acid.

N-Acetylneuraminic acid (Neu5Ac), one of the abundant types of sialic acid, is an emerging anticancer agent owing to its ability to target selectins in the plasma membrane of cancer cells. Considering the functionality of Neu5Ac, obtaining novel Neu5Ac-conjugated materials with a selective and an enhanced antitumor activity has remained a challenge. Herein, we report the supramolecular materials of three novel amphiphiles composed of Neu5Ac as a hydrophilic segment and pyrene or adamantane as a hydrophobic segment. The synthetic amphiphiles 1, 2, and 3 self-assembled into ribbons, vesicles, and irregular aggregates in an aqueous solution, respectively. Among the materials, vesicles of amphiphile 2 showed the most substantial selectivity toward cancer cells, followed by cell death due to the production of reactive oxygen species by the pyrene group. The dual advantage of Neu5Ac-selectivity and the pyrene-cytotoxicity of vesicles of amphiphile 2 can provide a strategy for effective anticancer materials.

Anti-PD-L1 peptide-conjugated prodrug nanoparticles for targeted cancer immunotherapy combining PD-L1 blockade with immunogenic cell death.

Rationale: Cancer immunotherapy combining immune checkpoint blockade (ICB) with chemotherapeutic drugs has provided significant clinical advances. However, such combination therapeutic regimen has suffered from severe toxicity of both drugs and low response rate of patients. In this study, we propose anti-PD-L1 peptide-conjugated prodrug nanoparticles (PD-NPs) to overcome these obstacles of current cancer immunotherapy. Methods: The functional peptide, consisted of anti-PD-L1 peptide and cathepsin B-specific cleavable peptide, is conjugated to a doxorubicin (DOX), resulting in prodrug nanoparticles of PD-NPs via intermolecular interactions. The antitumor efficacy and immune responses with minimal side effects by PD-NPs combining PD-L1 blockade and ICD are evaluated in breast tumor models. Results: The PD-NPs are taken up by PD-L1 receptor-mediated endocytosis and then induce ICD in cancer cells by DOX release. Concurrently, PD-L1 blockade by PD-NPs disrupt the immune-suppressing pathway of cancer cells, resulting in proliferation and reinvigoration of T lymphocytes. In tumor models, PD-NPs accumulate within tumor tissues via enhanced permeability and retention (EPR) effect and induce immune-responsive tumors by recruiting a large amount of immune cells. Conclusions: Collectively, targeted tumor delivery of anti-PD-L1 peptide and DOX via PD-NPs efficiently inhibit tumor progression with minimal side effects.