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Fluorescent dye labeling is a common strategy to analyze the fate of administered nanoparticles in living organisms. However, to which extent the labeling processes can alter the original nanoparticle biodistribution has been so far neglected. In this work, two widely used fluorescent dye molecules, namely, ATTO488 (ATTO) and Sulfo-Cy5 (S-Cy5), have been covalently attached to a well-characterized CXCR4-targeted self-assembling protein nanoparticle (known as T22-GFP-H6). The biodistribution of labeled T22-GFP-H6-ATTO and T22-GFP-H6-S-Cy5 nanoparticles has been then compared to that of the non-labeled nanoparticle in different CXCR4+ tumor mouse models. We observed that while parental T22-GFP-H6 nanoparticles accumulated mostly and specifically in CXCR4+ tumor cells, labeled T22-GFP-H6-ATTO and T22-GFP-H6-S-Cy5 nanoparticles showed a dramatic change in the biodistribution pattern, accumulating in non-target organs such as liver or kidney while reducing tumor targeting capacity. Therefore, the use of such labeling molecules should be avoided in target and non-target tissue uptake studies during the design and development of targeted nanoscale drug delivery systems, since their effect over the fate of the nanomaterial can lead to considerable miss-interpretations of the actual nanoparticle biodistribution.

As a multifunctional extracellular protein, connective tissue growth factor (CTGF/CCN2) is significantly associated with the progression and prognosis of triple‐negative breast cancer (TNBC). However, current blockade therapies targeting CTGF's multiple domains are limited, creating substantial challenges in treatment. Lysosome‐targeting chimeras (LYTACs) have emerged as a promising approach for achieving complete protein degradation and inhibiting CTGF's various bioactivities. In this study, a self‐assembling LYTAC nanoplatform, NanoCLY, designed to tumor microenvironment (TME)‐responsively degrade CTGF is presented. The complete degradation of CTGF downregulates the TGF‐β signaling pathway and disrupts the CTGF‐IL‐6 cell crosstalk within the TME, which further inhibits the activation of inflammatory cancer‐associated fibroblasts (CAFs) and alleviates the inflammatory TME. Notably, the anti‐TNBC effect of LYTAC‐based CTGF degradation therapy surpasses that of antibody‐based blockade therapy in both in vitro and in vivo models. The findings provide a proof of concept for CTGF degradation in TNBC and introduce the first CTGF‐LYTAC nanoplatform aimed at TME‐directed therapy. A CTGF‐LYTAC nanoplatform is developed to selectively degrade connective tissue growth factor (CTGF) in triple‐negative breast cancer (TNBC), inhibiting TGF‐β signaling and cell interactions in the tumor microenvironment (TME). This strategy effectively suppresses tumor growth and metastasis, outperforming antibody‐based therapy. The study provides proof of concept for CTGF degradation and introduces the first CTGF‐LYTAC nanoplatform for TME‐targeted TNBC treatment.

Oxidative stress (OS) contributes to nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. We investigated whether antioxidative self-assembling nanoparticles (SMAPoTN) could reduce the development of NASH and hepatocellular carcinoma (HCC) in p62/Sqstm1 and Nrf2 double knockout (DKO) mice and studied protective mechanisms. We measured disease development in male DKO mice fed a normal chow (NASH model) or a 60% high-fat diet (HFD; HCC model) with or without SMAPoTN administration for 26 weeks. SMAPoTN inhibited liver fibrosis in both groups and prevented HCC development (0% vs. 33%, p < 0.05) in the HFD group. SMAPoTN reduced OS, inflammatory cytokine signaling, and liver fibrosis. RNA-sequencing revealed that SMAPoTN decreased endoplasmic reticulum stress signaling genes in both groups, HCC driver genes, and cancer pathway genes, especially PI3K-AKT in the HFD groups. In the SMAPoTN treatment HFD group, serum lipopolysaccharide levels and liver lipopolysaccharide-binding protein expression were significantly lower compared with those in the nontreatment group. SMAPoTN improved the α-diversity of gut microbiota, and changed the microbiota composition. Oral SMAPoTN administration attenuated NASH development and suppressed hepatocarcinogenesis in DKO mice by improving endoplasmic reticulum stress in the liver and intestinal microbiota. SMAPoTN may be a new therapeutic option for NASH subjects and those with a high HCC risk.

Microfluidic techniques allow for the tailored construction of specific microparticles, which are becoming increasingly interesting and relevant. Here, using a microfluidic hole-plate-device and thermal-initiated free radical polymerization, submicrometer polymer particles with a highly textured surface were synthesized. Two types of monomers were applied: (1) methylmethacrylate (MMA) combined with crosslinkers and (2) divinylbenzene (DVB). Surface texture and morphology can be influenced by a series of parameters such as the monomer–crosslinker–solvent composition, surfactants, and additives. Generally, the most structured surfaces with the simultaneously most uniform particles were obtained in the DVB–toluene–nonionic-tensides system. In a second approach, poly-MMA (PMMA) particles were used to build aggregates with bigger polymer particles. For this purpose, tripropyleneglycolediacrylate (TPGDA) particles were synthesized in a microfluidic co-flow arrangement and polymerized by light- irradiation. Then, PMMA particles were assembled at their surface. In a third step, these composites were dispersed in an aqueous acrylamide–methylenebisacrylamide solution, which again was run through a co-flow-device and photopolymerized. As such, entities consisting of particles of three different size ranges—typically 0.7/30/600 µm—were obtained. The particles synthesized by both approaches are potentially suitable for loading with or incorporation of analytic probes or catalysts such as dyes or metals.

Fluorescent materials based on aggregation-induced emission luminogens (AIEgens) have unique advantages for in situ and real-time monitoring of biomolecules and biological processes because of their high luminescence intensity and resistance to photobleaching. Unfortunately, many AIEgens require time-consuming and expensive syntheses, and the presence of residual toxic reagents reduces their biocompatibility. Herein, silver@quercetin nanoparticles (Ag@QCNPs), which have a clear core–shell structure, were prepared by redox reaction of quercetin (QC), a polyphenolic compound widely obtained from plants, including those used as foods, and silver ions. Ag@QCNPs show both aggregation-induced luminescence and the distinct plasma scattering of silver nanoparticles, as well as good resistance to photobleaching and biocompatibility. The Ag@QCNPs were successfully used for cytoplasmic labeling of living cells and for computerized tomography imaging in tumor-bearing mice, demonstrating their potential for clinical applications.

With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1.

•Self-adjuvanting, self-assembling protein nanoparticle to prevent malaria is made.•Amounts of selected domains of flagellin per nanoparticle are optimized.•Immune responses and protective efficacy of the vaccine are determined. To eliminate the problems associated with the use of extraneous adjuvants we have designed a Self-Assembling Protein Nanoparticle (SAPN) containing epitopes from the Plasmodium falciparum circumsporozoite protein (PfCSP) (designated FMP014) and portions of the TLR5 agonist flagellin (designated FMP014D0D1) as an intrinsic adjuvant. By combining different molar ratios of FMP014 to FMP014D0D1 monomers before self-assembly, we generated multiple nanoparticles and investigated their biophysical characteristics, immunogenicity and protective efficacy. Immunization with the construct formulated with the ratio 58:2 of FMP014 to FMP014D0D1 had the highest protective efficacy against a challenge with a transgenic P. berghei sporozoite expressing PfCSP. Increasing the proportion of flagellin per particle resulted in an inverse relationship with levels of both antibody titers and protection. The cytokine profiles of the various immunization groups were evaluated and quantitative amounts of the cytokines IL-2, IFN-γ, IL-12/p70 (Th1); IL4, IL5 (Th2); TNF-α, IL1β, IL-6, KC/GRO (pro-inflammatory), and IL-10 (immunomodulatory) were measured. The relationship of the cytokines to each other revealed a strong immunomodulatory effect depending on the proportion of flagellin in the construct. Our results demonstrate that SAPNs with flagellin may be a promising strategy for the development and delivery of a safe vaccine for infectious diseases.

We describe the current Good Manufacturing Practice (cGMP) production and subsequent characterization of eOD-GT8 60mer, a glycosylated self-assembling nanoparticle HIV-1 vaccine candidate and germline targeting priming immunogen. Production was carried out via transient expression in the human embryonic kidney 293 (HEK293) cell line followed by a combination of purification techniques. A large-scale cGMP (200 L) production run yielded 354 mg of the purified eOD-GT8 60mer drug product material, which was formulated at 1 mg/mL in 10% sucrose in phosphate-buffered saline (PBS) at pH 7.2. The clinical trial material was comprehensively characterized for purity, antigenicity, glycan composition, amino acid sequence, and aggregation and by several safety-related tests during cGMP lot release. A comparison of the purified products produced at the 1 L scale and 200 L cGMP scale demonstrated the consistency and robustness of the transient transfection upstream process and the downstream purification strategies. The cGMP clinical trial material was tested in a Phase 1 clinical trial (NCT03547245), is currently being stored at −80 °C, and is on a stability testing program as per regulatory guidelines. The methods described here illustrate the utility of transient transfection for cGMP production of complex products such as glycosylated self-assembling nanoparticles.

The excessive use of antibiotics in recent years has contributed to an increase in microbial resistance, thereby compromising the health of both humans and animals and necessitating the development of innovative therapeutic strategies. In this study, we have creatively integrated fatty acids into the previously reported anti-enzymolysis unit (CRKP) in a branched configuration, resulting in the design and fabrication of a series of peptide dendritic with potent antifungal and anti-drug-resistant fungal activities. Notably, peptide dendron C 8 -2 exhibited significantly enhanced antifungal efficacy, favorable in vitro biocompatibility, and remarkable stability in the presence of serum and proteases. Mechanistic investigations reveal that C 8 -2 exert their antifungal effects by increasing cell wall permeability, inducing plasma membrane depolarization, leading to membrane rupture and content release, and generating reactive oxygen species. In addition, peptide dendron C 8 -2 can effectively eliminate Candida albicans from the eyeball in fungal-induced keratitis in mice, and the treatment effect is significantly superior to that of amphotericin B. Consequently, the self-assembled peptide dendron nanoparticles of C 8 -2 hold significant potential as antifungal agents. Additionally, their robust antifungal activity and stability against resistance may effectively address the growing challenge of drug-resistant fungal strains, thereby facilitating the development of future peptide nanoparticle-based therapies. Graphical abstract

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, self-assembling dextran-curcumin nanoparticles for the treatment of prostate cancer in combination therapy with Doxorubicin (DOXO). Biological effectiveness was investigated by evaluating the cell viability in either cancer and normal cells, reactive oxygen species (ROS) production, apoptotic effect, interference with the cell cycle, and the ability to inhibit cell migration and reverse the epithelial to mesenchymal transition (EMT). The results proved a significant enhancement of curcumin efficiency upon immobilization in nanoparticles: IC50 reduced by a half, induction of apoptotic effect, and improved ROS production (from 67 to 134%) at low concentrations. Nanoparticles guaranteed a pH-dependent DOXO release, with a more efficient release in acidic environments. Finally, a synergistic effect between nanoparticles and Doxorubicin was demonstrated, with the free curcumin showing additive activity. Although in vivo studies are required to support the findings of this study, these preliminary in vitro data can be considered a proof of principle for the design of an effective therapy for prostate cancer treatment.