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Multimodal therapy requires effective drug carriers that can deliver multiple drugs to specific locations in a controlled manner. Here, the study presents a novel nanoplatform constructed using zeolitic imidazolate framework‐8 ( Z IF‐8), a nanoscale metal‐organic framework nucleated under the mediation of silk fibroin ( S F). The nanoplatform is modified with the newly discovered MCF‐7 breast tumor‐targeting peptide, AREYGTRFSLIGGYR ( AR peptide). Indocyanine green ( I CG) and doxorubicin ( D OX) are loaded onto the nanoplatform with high drug encapsulation efficiency (>95%). ICG enables the resultant nanoparticles (NPs), called AR‐ZS/ID‐P, to release reactive oxygen species for photodynamic therapy ( P DT) and heat for photothermal therapy ( P TT) under near‐infrared (NIR) irradiation, promoting NIR fluorescence and thermal imaging to guide DOX‐induced chemotherapy. Additionally, the controlled release of both ICG and DOX at acidic tumor conditions due to the dissolution of ZIF‐8 provides a drug‐targeting mechanism in addition to the AR peptide. When intravenously injected, AR‐ZS/ID‐P NPs specifically target breast tumors and exhibit higher anticancer efficacy than other groups through ICG‐enabled PDT and PTT and DOX‐derived chemotherapy, without inducing side effects. The results demonstrate that AR‐ZS/ID‐P NPs are a promising multimodal theranostic nanoplatform with maximal therapeutic efficacy and minimal side effects for targeted and controllable drug delivery.

Small‐interfering RNA (siRNA) therapy is considered a powerful therapeutic strategy for treating cardiac hypertrophy, an important risk factor for subsequent cardiac morbidity and mortality. However, the lack of safe and efficient in vivo delivery of siRNAs is a major challenge for broadening its clinical applications. Small extracellular vesicles (sEVs) are a promising delivery system for siRNAs but have limited cell/tissue‐specific targeting ability. In this study, a new generation of heart‐targeting sEVs (CEVs) has been developed by conjugating cardiac‐targeting peptide (CTP) to human peripheral blood‐derived sEVs (PB‐EVs), using a simple, rapid and scalable method based on bio‐orthogonal copper‐free click chemistry. The experimental results show that CEVs have typical sEVs properties and excellent heart‐targeting ability. Furthermore, to treat cardiac hypertrophy, CEVs are loaded with NADPH Oxidase 4 (NOX4) siRNA (siNOX4). Consequently, CEVs@siNOX4 treatment enhances the in vitro anti‐hypertrophic effects by CEVs with siRNA protection and heart‐targeting ability. In addition, the intravenous injection of CEVs@siNOX4 into angiotensin II (Ang II)‐treated mice significantly improves cardiac function and reduces fibrosis and cardiomyocyte cross‐sectional area, with limited side effects. In conclusion, the utilization of CEVs represents an efficient strategy for heart‐targeted delivery of therapeutic siRNAs and holds great promise for the treatment of cardiac hypertrophy.

To ensure compositional consistency while mitigating potential immunogenicity for stem cell therapy, synthetic scaffolds have emerged as compelling alternatives to native extracellular matrix (ECM). Substantial progress has been made in emulating specific natural traits featuring consistent chemical compositions and physical structures. However, recapitulating the dynamic responsiveness of the native ECM involving chemical transitions and physical remodeling during differentiation, remains a challenging endeavor. Here, the creation of adaptive scaffolds is demonstrated through sequential protein‐instructed molecular assembly, utilizing stage‐specific proteins, and incorporating in situ assembly technique. The procedure is commenced by introducing a dual‐targeting peptide at the onset of stem cell differentiation. In response to highly expressed integrins and heparan sulfate proteoglycans (HSPGs) on human mesenchymal stem cell (hMSC), the peptides assembled in situ, creating customized extracellular scaffolds that adhered to hMSCs promoting osteoblast differentiation. As the expression of alkaline phosphatase (ALP) and collagen (COL‐1) increased in osteoblasts, an additional peptide is introduced that interacts with ALP, initiating peptide assembly and facilitating calcium phosphate (CaP) deposition. The growth and entanglement of peptide assemblies with collagen fibers efficiently incorporated CaP into the network resulting in an adaptive biphasic scaffold that enhanced healing of bone injuries. Utilizing a sequential protein‐instructed molecular assembly approach, adaptive scaffolds are developed that emulate the dynamic responsiveness of the native extracellular matrix (ECM). By incorporating peptides interacting with stage‐specific proteins during osteogenesis, the scaffolds demonstrate remarkable adaptability to the everchanging cellular microenvironment enhancing bone injury healing.

Background Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV) has led to serious economic losses to the swine industry worldwide. In this study, an oral recombinant Lactobacillus casei vaccine against PEDV infection targeting the intestinal microfold (M) cells and dendritic cells (DCs) for delivering the core neutralizing epitope (COE) of PEDV spike protein was developed with M cell-targeting peptide (Col) and dendritic cell-targeting peptide (DCpep). The immunogenicity of the orally administered recombinant strains was evaluated. Results After immunization, significantly higher levels of anti-PEDV specific IgG antibodies with PEDV neutralizing activity in the sera and mucosal sIgA antibodies in the tractus genitalis, intestinal mucus, and stools were detected in mice orally administered with the recombinant strain pPG-COE-Col-DCpep/L393, which expressed DCpep and Col targeting ligands fused with the PEDV COE antigen, compared to mice orally immunized with the recombinant strain pPG-COE/L393 without the DCpep and Col targeting ligands. Moreover, in response to restimulation with the PEDV COE antigen in vitro, a significant difference in splenocyte proliferation response and Th2-associated cytokine IL-4 level was observed in the group of mice orally immunized with pPG-COE-Col-DCpep/L393 ( p  < 0.05) compared to the groups of mice that received pPG-COE-Col/L393 and pPG-COE-DCpep/L393, respectively. Conclusions The intestinal M cells- and DCs-targeting oral delivery of genetically engineered Lactobacillus expressing the COE antigen of PEDV can efficiently induce anti-PEDV mucosal, humoral, and cellular immune responses via oral administration, suggesting a promising vaccine strategy against PEDV infection.

Porcine epidemic diarrhea virus (PEDV) is a highly infectious virus that leads to severe diarrhea and high death rates in neonatal piglets. Because PEDV primarily infects the intestinal mucosa, the induction of effective mucosal immunity through oral vaccination represents a promising strategy for disease prevention. In this study, a recombinant Lactobacillus paracasei (L. paracasei) strain expressing a multicomponent fusion antigen composed of the PEDV S1 protein, M cell- and dendritic cell-targeting peptides, and the mucosal adjuvant LTB was constructed as a candidate oral vaccine. Pregnant mice orally immunized with the recombinant strain exhibited significantly increased levels of PEDV-specific serum IgG as well as secretory IgA (SIgA) in intestinal mucus and feces, both of which showed in vitro neutralizing activity. In addition, oral immunization markedly enhanced cellular immune responses, as indicated by elevated serum levels of IFN-γ, IL-2, IL-4, and IL-10. Notably, newborn mice delivered by immunized dams displayed significantly higher levels of PEDV-specific SIgA, demonstrating effective maternal antibody transfer. These results indicate that the recombinant L. paracasei strain can robustly induce humoral, cellular, and mucosal immune responses and confer maternal immune protection. This study emphasizes the possibility of oral vaccinations based on L. paracasei as a viable approach to the prevention and management of epidemic diarrhea in piglets.

Peptide nucleic acids (PNAs) are very useful tools for gene regulation at different levels, but in particular in the last years their use for targeting microRNA (anti-miR PNAs) has provided impressive advancements. In this respect, microRNAs related to the repression of cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is defective in cystic fibrosis, are of great importance in the development of new type of treatments. In this paper we propose the use of an anti-miR PNA for targeting miR-145, a microRNA reported to suppress CFTR expression. Octaarginine-anti-miR PNA conjugates were delivered to Calu-3 cells, exerting sequence dependent targeting of miR-145-5p. This allowed to enhance expression of the miR-145 regulated CFTR gene, analyzed at mRNA (RT-qPCR, Reverse Transcription quantitative Polymerase Chain Reaction) and CFTR protein (Western blotting) level.

Cancer is currently ineffectively treated using therapeutic drugs, and is also able to resist drug action, resulting in increased side effects following drug treatment. A novel therapeutic strategy against cancer cells is the use of anticancer peptides (ACPs). The physicochemical properties, amino acid composition and the addition of chemical groups on the ACP sequence influences their conformation, net charge and orientation of the secondary structure, leading to an effect on targeting specificity and ACP-cell interaction, as well as peptide penetrating capability, stability and efficacy. ACPs have been developed from both naturally occurring and modified peptides by substituting neutral or anionic amino acid residues with cationic amino acid residues, or by adding a chemical group. The modified peptides lead to an increase in the effectiveness of cancer therapy. Due to this effectiveness, ACPs have recently been improved to form drugs and vaccines, which have sequentially been evaluated in various phases of clinical trials. The development of the ACPs remains focused on generating newly modified ACPs for clinical application in order to decrease the incidence of new cancer cases and decrease the mortality rate. The present review could further facilitate the design of ACPs and increase efficacious ACP therapy in the near future.

Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency.

The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention. The oncolytic peptide LTX-315 derived from bovine lactoferricin (LfcinB) was found to be highly effective against suspension cancer cells, but not adherent cancer cells. In this study, we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells. Thus, four hybrid peptides, NTP-212, NTP-217, NTP-223 and NTP-385, were synthesized. These hybrid peptides enhanced the anticancer activity of LTX-315 in a panel of adherent cancer cell lines by 2.4- to 37.5-fold. In model mice bearing B16-F10 melanoma xenografts, injection of NTP-385 (0.5 mg per mouse for 3 consecutive days) induced almost complete regression of melanoma, prolonged the median survival time and increased the overall survival. Notably, the administered dose of NTP-385 was only half the effective dose of LTX-315. We further revealed that unlike LTX-315, which targets the mitochondria, NTP-385 disrupted the nuclear membrane and accumulated in the nucleus, resulting in the transfer of a substantial amount of reactive oxygen species (ROS) from the cytoplasm to the nucleus through the fragmented nuclear membrane. This ultimately led to DNA double-strand break (DSB)-mediated intrinsic apoptosis. In conclusion, this study demonstrates that hybrid peptides obtained from the fusion of LTX-315 and rhodamine B enhance anti-adherent cancer cell activity by targeting the nucleus and triggering DNA DSB-mediated intrinsic apoptosis. This study also provides an advantageous reference for nucleus-targeting peptide modification. Nucleus-targeting hybrid peptides obtained by fusing LTX-315 with rhodamine B inflicted DNA double-strand break (DSB)-mediated intrinsic apoptosis by destroying the nuclear membrane and inducing the accumulation of reactive oxygen species (ROS) in the nucleus.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor, and the clinically available approaches for its treatment are not curative. Despite the intensive research, biological barriers such as the blood–brain barrier (BBB) and tumor cell membranes are major obstacles to developing novel effective therapies. Nanoparticles (NPs) have been explored as drug delivery systems (DDS) to improve GBM therapeutic strategies. NPs can circumvent many of the biological barriers posed by this devastating disease, enhancing drug accumulation in the target site. This can be achieved by employing strategies to target the transferrin receptor (TfR), which is heavily distributed in BBB and GBM cells. These targeting strategies comprise the modification of NPs’ surface with various molecules, such as transferrin (Tf), antibodies, and targeting peptides. This review provides an overview and discussion on the recent advances concerning the strategies to target the TfR in the treatment of GBM, as their benefits and limitations.