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A major challenge in immunotherapy is the inability to reliably predict patient responses due to the lack of robust biomarkers. Programmed cell death‐ligand 1 (PD‐L1)–expressing exosomes represent a promising biomarker candidate; however, existing detection platforms lack the sensitivity and specificity required for clinical translation. It is hypothesized that an avidity‐based capture strategy utilizing dendrimer‐mediated multivalent binding will effectively enhance molecular avidity and improve the selective capture of PD‐L1‐expressing exosomes. Supporting this hypothesis, atomic force microscopy (AFM) revealed that dendrimer–peptide conjugates synthesized using generation 7 poly(amidoamine) dendrimers (G7‐pPDL1) exhibited ≈2.48‐fold higher binding avidity than conventional anti‐PD‐L1 antibodies (aPD‐L1), attributed to multivalent interactions. This increased avidity led to enhanced in vitro specificity and enabled 1.55‐fold greater sensitivity in capturing PD‐L1‐expressing exosomes, compared to aPD‐L1. Clinical validation using serum samples from patients undergoing immune checkpoint inhibitor therapy demonstrated that PD‐L1‐expressing exosomes captured using the G7‐pPD‐L1 surface more accurately predicted treatment response and outperformed tissue‐based PD‐L1 scoring in prognostic value. Additionally, this platform is compatible with existing biosensing technologies and enables real‐time exosome detection with a limit of detection as low as 9.6 × 101 vesicles mL−1. Taken together, these findings highlight the versatility and clinical promise of this avidity‐based capture strategy for advancing precision immunotherapy. This study introduces a dendrimer‐peptide conjugate platform (G7‐pPDL1) for avidity‐based capture of PD‐L1‐expressing exosomes. The system exhibits enhanced binding kinetics and exosome capture efficiency, enabling accurate prediction of immunotherapy outcomes. Its integration with biosensors further demonstrates potential for sensitive, real‐time exosome detection and broad applicability in precision cancer immunotherapy.

Bufalin (BFL) has excellent physiological activities such as defending tumors, improving cardiac function, and so on. However, due to its poor water-solubility and bioavailability, the clinical application of BFL remains limited. In order to improve bioavailability of BFL, in our previous research, a novel peptide-dendrimer (PD) was synthesized and applied to encapsulate BFL. In the present study, we investigate the absorption property and mechanism of BFL in free form and BFL-peptide-dendrimer inclusion (BPDI) delivery system by using the Caco-2 cell monolayer model in vitro. The apparent permeability coefficient (Papp) values of BFL in free or BPDI form were over 1.0 × 10−6 cm/s. Meanwhile, their almost equal bi-directional transport and linear transport percentage with time and concentration course indicated that BFL in both forms was absorbed mainly through passive diffusion. The most important result is that the Papp values of BFL increased about three-fold more BPDI than those of its free form, which indicated the intestinal permeability of BFL could be improved while BFL was encapsulated in BPDI form. Therefore, PD encapsulation may be a potential delivery system to increase the bioavailability of BFL.

Asenapine maleate (ASPM) is a second-generation atypical antipsychotic that is approved for treating acute schizophrenia and bipolar disorder in adults by the US FDA. The major downside of ASPM therapy is rapid, extensive first-pass hepatic metabolism following its oral administration with a very low oral bioavailability of < 2%. In this work, we developed ASPM nanoformulations conjugated with ligands such as arginine-glycine-aspartic acid (RGD) and peptide dendrimers (PDs) with the intention of improving the oral bioavailability of the drug by targeting it to the intestinal lymphatic system (ILS). Peptide dendrimers (PDs), both lipidated and nonlipidated, were synthesized by Fmoc solid phase peptide synthesis (SPPS). Reverse phase high performance chromatography (RP-HPLC) was used to purify the synthesized PDs, and the PDs were characterized by differential scanning calorimetry (DSC) electrospray ionization mass spectroscopy (ESI + -MS), Nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy. The thin film hydration method was used to prepare liposomes, and the process variables affecting the liposome parameters were optimized using the Box‒Behnken design (BBD).Liposomes were PEGylated using DSPE-PEG-COOH 2000 and further conjugated with ligands (RGD, PD-1 and PD-2) using EDC-NHS chemistry. The formulation was characterized using different spectroscopic techniques. In vitro, cell line studies, such as cytotoxicity, cell uptake, uptake mechanism, and receptor saturation studies, were performed on both Caco2 and Raji-B cells. The pharmacokinetic parameters of the developed liposomal formulation were evaluated using pharmacokinetic studies on Sprague- Dawley (SD) rats. The psychostimulant-induced hyperactivity model was used to evaluate the pharmacodynamic performance of the developed formulations by measuring the reversal of hyperlocomotor activity induced by levodopa-carbidopa.

Peptides displaying antimicrobial properties are being regarded as useful tools to evade and combat antimicrobial resistance, a major public health challenge. Here we have addressed dendrimers, attractive molecules in pharmaceutical innovation and development displaying broad biological activity. Triazine-based dendrimers were fully synthesized in the solid phase, and their antimicrobial activity and some insights into their mechanisms of action were explored. Triazine is present in a large number of compounds with highly diverse biological targets with broad biological activities and could be an excellent branching unit to accommodate peptides. Our results show that the novel peptide dendrimers synthesized have remarkable antimicrobial activity against Gram-negative bacteria (E. coli and P. aeruginosa) and suggest that they may be useful in neutralizing the effect of efflux machinery on resistance.

In this paper we study two lysine-based peptide dendrimers with Lys-His-Arg and Lys-Arg-His repeating units and terminal lysine groups. Combination of His and Arg properties in a dendrimer could be important for biomedical applications, especially for prevention of dendrimer aggregation and for penetration of dendrimers through various cell membranes. We describe the synthesis of these dendrimers and the confirmation of their structure using 1D and 2D Nuclear Magnetic Resonance (NMR) spectroscopy. NMR spectroscopy and relaxation are used to study the structural and dynamic properties of these macromolecules and to compare them with properties of previously studied dendrimers with Lys-2Arg and Lys-2His repeating units. Our results demonstrate that both Lys-His-Arg and Lys-Arg-His dendrimers have pH sensitive conformation and dynamics. However, properties of Lys-His-Arg at normal pH are more similar to those of the more hydrophobic Lys-2His dendrimer, which has tendency towards aggregation, while the Lys-Arg-His dendrimer is more hydrophilic. Thus, the conformation with the same amino acid composition of Lys-His-Arg is more pH sensitive than Lys-Arg-His, while the presence of Arg groups undoubtedly increases its hydrophilicity compared to Lys-2His. Hence, the Lys-His-Arg dendrimer could be a more suitable (in comparison with Lys-2His and Lys-Arg-His) candidate as a pH sensitive nanocontainer for drug delivery.

Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to the pathogenesis of inflammatory bowel disease (IBD). Current first‐line treatments for IBD have limited efficacy and significant side effects. An innovative H2S‐releasing montmorillonite nanoformulation (DPs@MMT) capable of remodeling intestinal mucosal immune homeostasis, repairing the mucosal barrier, and modulating gut microbiota is developed by electrostatically adsorbing diallyl trisulfide‐loaded peptide dendrimer nanogels (DATS@PDNs, abbreviated as DPs) onto the montmorillonite (MMT) surface. Upon rectal administration, DPs@MMT specifically binds to and covers the damaged mucosa, promoting the accumulation and subsequent internalization of DPs by activated immune cells in the IBD site. DPs release H2S intracellularly in response to glutathione, initiating multiple therapeutic effects. In vitro and in vivo studies have shown that DPs@MMT effectively alleviates colitis by eliminating reactive oxygen species (ROS), inhibiting inflammation, repairing the mucosal barrier, and eradicating pathogens. RNA sequencing revealed that DPs@MMT exerts significant immunoregulatory and mucosal barrier repair effects, by activating pathways such as Nrf2/HO‐1, PI3K‐AKT, and RAS/MAPK/AP‐1, and inhibiting the p38/ERK MAPK, p65 NF‐κB, and JAK‐STAT3 pathways, as well as glycolysis. 16S rRNA sequencing demonstrated that DPs@MMT remodels the gut microbiota by eliminating pathogens and increasing probiotics. This study develops a promising nanoformulation for IBD management. An H2S‐releasing montmorillonite nanoformulation (DPs@MMT) is developed by adsorbing diallyl trisulfide‐loaded peptide dendrimer nanogels onto the MMT surface. DPs@MMT can remodel intestinal mucosal immune homeostasis by activating Nrf2/HO‐1 and PI3K‐AKT pathways, inhibiting p38/ERK MAPK, p65 NF‐κB, and JAK‐STAT3 pathways along with HIF‐1‐induced glycolysis; repair mucosal barrier by activating RAS/MAPK/AP‐1 pathway; and modulate gut microbiota by eliminating pathogens and increasing probiotics.

The clinical efficacy of personalized cancer vaccines still needs to be improved due to their insufficient immune effect. The development of innovative adjuvants and lymph node‐targeted delivery systems is the key to improving the clinical efficacy of personalized vaccines. However, there is still a lack of an adjuvant delivery system that is simple in preparation and capable of mass production and integrates adjuvant and lymph node targeted delivery functions. Here, this work reports that a simple dendrimer polypeptide (KK2DP7) nanoparticle enhances the immune efficacy of an OVA/neoantigen‐based vaccine. Due to its multiple functions as a delivery vehicle, immune adjuvant, and facilitator of dendritic cell migration, KK2DP7 efficiently increases the efficiency of antigen uptake and cross‐presentation by antigen‐presenting cells (APCs) and delivers antigens to lymph nodes via APCs. Strikingly, the antitumor effect of KK2DP7/OVA is superior to that of commonly used adjuvants such as poly(I:C), CpG, and aluminum adjuvant combined with OVA. Furthermore, KK2DP7/OVA combined with anti‐PD‐1 antibody is able to prevent tumor recurrence in a postoperative recurrent tumor model. Thus, KK2DP7‐based cancer vaccines alone or in combination with immune checkpoint blockade therapies to treat tumors or postoperative tumor recurrence are a powerful strategy to enhance antitumor immunity. KK2DP7 in combination with OVA can form nanovaccine that can target lymph nodes after subcutaneous injection. As a delivery vehicle, it can efficiently deliver OVA to DCs via caveolin‐ and clathrin‐dependent pathways. As an immune adjuvant, it can stimulate DC maturation by activating the TLR2‐NF‐κB signaling pathway, increasing the efficiency of DC cross‐presentation to antigens and inducing subsequent immune responses.

Glaucoma, a leading cause of irreversible blindness, is characterized by retinal ganglion cell (RGC) degeneration due to elevated intraocular pressure (IOP) and apoptosis. While timolol maleate effectively lowers IOP, it does not prevent RGC loss and suffers from poor corneal permeability and rapid clearance. This study introduces a novel dual-delivery nanovesicular system employing multifunctional spanlastics to simultaneously lower IOP and inhibit RGC apoptosis via caspase-2 gene silencing. The system comprises two distinct nanovesicle populations: (i) timolol-loaded vesicles conjugated with peptide dendrimers to enhance corneal penetration and anterior segment delivery; and (ii) siRNA-loaded vesicles targeting Caspase-2, coated with hyaluronic acid for posterior segment delivery and gene silencing. This is the first approach integrating IOP reduction with targeted genetic intervention to protect RGCs. Formulations were optimized using a Design of Experiments approach and showed desirable physicochemical properties, sustained release, improved transcorneal permeability, and 1-month stability at 4 °C. In vitro studies confirmed Caspase-2 silencing and apoptosis reduction in RGC-5 cells, while in vivo results demonstrated prolonged IOP control. Safety was confirmed via histopathological and ocular irritation assessments. This targeted, non-invasive dual-delivery platform offers a promising therapeutic strategy for comprehensive glaucoma management.

Due to their intrinsic anti‐inflammatory and immunomodulatory properties, adipose‐derived stem cells (ADSCs) are explored as a promising alternative in treating rheumatoid arthritis (RA). To address the poor survival and function loss of directly injected stem cells, efforts in this area are focus on the generation of efficient cell delivery vehicles. Herein, a novel extracellular matrix (ECM)‐inspired injectable hydrogel for ADSCs encapsulation and RA treatment is proposed. The hydrogel with dendritic polylysine and polysaccharide components is formed through the reversible Schiff base crosslinking. It possesses self‐healing capability, superior mechanical properties, minimal toxicity, and immunomodulatory ability. When encapsulated with ADSCs, the hydrogel could recover chronic inflammation by directly reversing the dominant macrophage phenotype from M1 to M2 and inhibiting the migration of fibroblast‐like synoviocytes. Through a collagen‐induced arthritis rat model, the tremendous therapeutic outcomes of this ADSCs‐laden hydrogel, including inflammation attenuation, cartilage protection, and bone mineral density promotion are demonstrated. These results make the ECM‐inspired hydrogel laden with ADSCs an ideal candidate for treating RA and other autoimmune disorders. A novel extracellular matrix (ECM)‐inspired hydrogel for adipose‐derived stem cells (ADSCs) encapsulation and rheumatoid arthritis (RA) treatment is developed. The hydrogel demonstrates self‐healing capability, superior mechanical properties, minimal toxicity, and immunomodulatory ability. In a collegan‐induced arthritis model, the ADSCs‐laden hydrogel displays great therapeutic outcomes, indicating its great potential for treating RA.

Novel peptide dendrimer with Lys-2His repeating units was recently synthesized, studied by NMR (Molecules, 2019, 24, 2481) and tested as a nanocontainer for siRNA delivery (Int. J. Mol. Sci., 2020, 21, 3138). Histidine amino acid residues were inserted in the spacers of this dendrimer. Increase of their charge with a pH decrease turns a surface-charged dendrimer into a volume-charged one and should change all properties. In this paper, the molecular dynamics simulation method was applied to compare the properties of the dendrimer in water with explicit counterions at two different pHs (at normal pH with neutral histidines and at low pH with fully protonated histidines) in a wide interval of temperatures. We obtained that the dendrimer at low pH has essentially larger size and size fluctuations. The electrostatic properties of the dendrimers are different but they are in good agreement with the theoretical soft sphere model and practically do not depend on temperature. We have shown that the effect of pairing of side imidazole groups is much stronger in the dendrimer with neutral histidines than in the dendrimer with protonated histidines. We also demonstrated that the capacity of a nanocontainer based on this dendrimer with protonated histidines is significantly larger than that of a nanocontainer with neutral histidines.