Synthetic-polymer-assisted antisense oligonucleotide delivery: targeted approaches for precision disease treatment

• Ana Cubillo Alvarez,
• Dylan Maguire and
• Ruairí P. Brannigan

Beilstein J. Nanotechnol. 2025, 16, 435–463, doi:10.3762/bjnano.16.34

• potential in precision disease treatment. Synthetic polymers have shown significant promise in enhancing the delivery, stability, and therapeutic efficacy of ASOs by addressing key challenges such as cellular uptake, endosomal escape, and reducing cytotoxicity. The review highlights key studies from the

• of these DPL–ASO complexes to achieve nuclear localisation, although some challenges remain regarding endosomal escape and complete nuclear delivery. Le et al. recently investigated the targeted delivery of ASOs through the conjugation of cyclic RGD and iRGD peptides to the DPL structure [78]. This

• and limits the therapeutic efficacy of ASOs as nuclear access is often crucial for their intended function. Therefore, strategies focused on promoting endosomal escape and enhancing nuclear delivery are crucial for improving the uptake efficiency of lysine-conjugated ASOs and maximising their

Nanocarriers and macrophage interaction: from a potential hurdle to an alternative therapeutic strategy

• Naths Grazia Sukubo,
• Paolo Bigini and
• Annalisa Morelli

Beilstein J. Nanotechnol. 2025, 16, 97–118, doi:10.3762/bjnano.16.10

• uptake and enabling the endosomal escape To improve the efficacy of NC-based drug delivery systems, it is crucial to develop strategies that reduce macrophage uptake and extend NC circulation time. This could be achieved by acting on NCs exploiting alternative administration routes or physicochemical

• . Coating NCs with membranes from red blood cells or neutrophils or decorating them with peptides can camouflage the NCs and prevent macrophage ingestion [51][52]. 4.4 Endosomal escape After reaching the target site, as discussed in the previous paragraphs, NCs should release their cargo to exert their

• final effect. Endocytosis poses a significant challenge for delivering drugs and nucleic acids to the cytosol as most remain trapped in endosomes and subsequently degrade. Efficient delivery requires the payload to be released before lysosomal maturation, a crucial stage known as endosomal escape [53

Mechanistic insights into endosomal escape by sodium oleate-modified liposomes

• Ebrahim Sadaqa,
• Satrialdi,
• Fransiska Kurniawan and
• Diky Mudhakir

Beilstein J. Nanotechnol. 2024, 15, 1667–1685, doi:10.3762/bjnano.15.131

• .15.131 Abstract Endosomal entrapment significantly limits the efficacy of drug delivery systems. This study investigates sodium oleate-modified liposomes (SO-Lipo) as an innovative strategy to enhance endosomal escape and improve cytosolic delivery in 4T1 triple-negative breast cancer cells. We aimed to

• elucidate the mechanistic role of sodium oleate in promoting endosomal escape and compared the performance of SO-Lipo with unmodified liposomes (Unmodified-Lipo) and Aurein 1.2-modified liposomes (AUR-Lipo). Liposomes were prepared using the thin-film hydration method, resulting in Unmodified-Lipo, SO-Lipo

• , and AUR-Lipo formulations. The particle sizes were 102.2 ± 3.30 nm for Unmodified-Lipo, 109.6 ± 7.65 nm for SO-Lipo, and 151.9 ± 5.88 nm for AUR-Lipo, with polydispersity indices below 0.25, indicating uniform size distribution. Endosomal escape efficiency was evaluated through confocal microscopy by

The steep road to nonviral nanomedicines: Frequent challenges and culprits in designing nanoparticles for gene therapy

• Yao Yao,
• Yeongun Ko,
• Grant Grasman,
• Jeffery E. Raymond and
• Joerg Lahann

Beilstein J. Nanotechnol. 2023, 14, 351–361, doi:10.3762/bjnano.14.30

• studies. Regardless of the uptake pathway, the current understanding of how NPs induce endosomal escape lags behind and is limited by the current techniques used to detect it. Thus, new and accurate endosomal escape assays are required to understand the relationship between NP composition and endosomal

• escape. NAT are difficult to quantify if encapsulated into NP delivery carriers. The most common forms of nucleic acid measurement (i.e., UV–vis and fluorescence) provide limited insights for the characterization of NP-encapsulated NATs. Labeling and destructive methods both have drawbacks, ranging from

Nanotechnology – a robust tool for fighting the challenges of drug resistance in non-small cell lung cancer

• Filip Gorachinov,
• Fatima Mraiche,
• Diala Alhaj Moustafa,
• Ola Hishari,
• Yomna Ismail,
• Jensa Joseph,
• Maja Simonoska Crcarevska,
• Marija Glavas Dodov,
• Nikola Geskovski and
• Katerina Goracinova

Beilstein J. Nanotechnol. 2023, 14, 240–261, doi:10.3762/bjnano.14.23

• demonstrated pH-dependent selective survivin-shRNA release in the acidic environment after endosomal escape and disassembly to single PAMAM nanoparticles showing continuous release of erlotinib and chloroquine. Chloroquine has a dual effect on the efficacy. It improves vascular barrier integrity and together

• with PAMAM, facilitates endosomal escape. Down-regulation of survivin reverses EGFR TKI resistance in T790M mutant NSCLC cells and sensitizes the tumor to erlotinib. The synergy of survivin and EGFR downregulation coupled with decreased angiogenesis results in significant inhibition of proliferation

• , localization, internalization, and endosomal escape. This will increase the potency of the NPs. The FIND project is a high-throughput approach to identify and define the rational design of LNPs for functional delivery of mRNA to the liver and non-liver tissues and targeted gene editing. Structure–activity

Cyclodextrins as eminent constituents in nanoarchitectonics for drug delivery systems

• Makoto Komiyama

Beilstein J. Nanotechnol. 2023, 14, 218–232, doi:10.3762/bjnano.14.21

• ′-direction to provide an overhang in both ends. Thus, the siRNA was captured by two kinds of antisense DNAs on the β-CyDs through RNA/DNA hybridization and co-assembled to the nanoparticles. Folic acid (for targeting tumors) and an influenza hemagglutinin peptide HA (for endosomal escape) were conjugated

• influenza hemagglutinin peptide HA (for endosomal escape) by inclusion complex formation of β-CyD with adamantane. In human cells, the RNA/DNA hybrid was digested by intracellular ribonuclease H to release the antisense DNA. Furthermore, the linker is divided into three portions through the cleavage of two

Systematic studies into uniform synthetic protein nanoparticles

• Nahal Habibi,
• Ava Mauser,
• Jeffery E. Raymond and
• Joerg Lahann

Beilstein J. Nanotechnol. 2022, 13, 274–283, doi:10.3762/bjnano.13.22

• response at the cellular level. Several studies [28][29][30] have shown that considerations such as aspect ratio, stiffness/deformability, and particle surface roughness (deviation of circularity) can have a comparable impact on cellular uptake and/or endosomal escape. Hence, it is important to incorporate

Comprehensive review on ultrasound-responsive theranostic nanomaterials: mechanisms, structures and medical applications

• Sepand Tehrani Fateh,
• Lida Moradi,
• Elmira Kohan,
• Michael R. Hamblin and
• Amin Shiralizadeh Dezfuli

Beilstein J. Nanotechnol. 2021, 12, 808–862, doi:10.3762/bjnano.12.64

Applications of superparamagnetic iron oxide nanoparticles in drug and therapeutic delivery, and biotechnological advancements

• Maria Suciu,
• Corina M. Ionescu,
• Alexandra Ciorita,
• Septimiu C. Tripon,
• Dragos Nica,
• Hani Al-Salami and
• Lucian Barbu-Tudoran

Beilstein J. Nanotechnol. 2020, 11, 1092–1109, doi:10.3762/bjnano.11.94

• endosomal escape [113][114]. For the specific treatment of cisplatin-resistant nasopharyngeal carcinoma, Weng et al. [115] produced SPIONs covered with cisplatin and with TAT peptide (a HIV-derived cell penetrating peptide). Their nanoparticles had an increased endocytosis rate, which, combined with the

Poly(1-vinylimidazole) polyplexes as novel therapeutic gene carriers for lung cancer therapy

• Gayathri Kandasamy,
• Elena N. Danilovtseva,
• Vadim V. Annenkov and
• Uma Maheswari Krishnan

Beilstein J. Nanotechnol. 2020, 11, 354–369, doi:10.3762/bjnano.11.26

• the hepatocyte surface through the lactosylated poly(ʟ-lysine). The endosomal escape was mediated through a pH-responsive protonation of the imidazole and amino moieties that disrupted the endosomal membrane [17]. Zinc–PVI systems have also been investigated for complexing DNA for gene delivery

• attempted to investigate the DNA complexation efficiency of poly(4-vinylimidazole) polymers that also possesses low cytotoxicity and good endosomal escape properties [20]. To our knowledge, only few proof-of-concept studies have been carried out to explore the potential of PVI as a cyto-compatible gene

• delivery applications. The imidazole moieties in PVI can neutralize the acidic pH value, which in turn can aid their endosomal escape through the proton sponge mechanism, through altering the membrane permeability or through by-passing the endosomes [26]. However, the confocal images also reveal that a

Internalization mechanisms of cell-penetrating peptides

• Ivana Ruseska and
• Andreas Zimmer

Beilstein J. Nanotechnol. 2020, 11, 101–123, doi:10.3762/bjnano.11.10

• the plasma membrane and involves two distinct steps: endocytic uptake followed by endosomal escape [51]. Endocytosis is a complex process composed of more than one mechanism and is generally divided into two categories: phagocytosis and pinocytosis. Phagocytosis involves the uptake of large particles

Targeting strategies for improving the efficacy of nanomedicine in oncology

• Gonzalo Villaverde and
• Alejandro Baeza

Beilstein J. Nanotechnol. 2019, 10, 168–181, doi:10.3762/bjnano.10.16

• endosomal escape to reach the cytosol. Multiple strategies for overcoming the endosomal entrapment have been designed [52]. One of the most widely employed is the incorporation of polycationic groups on the particle surface such as poly(ethyleneimine), cationic dendrimers or poly(histidine) chains [53

• another mechanism for inducing endosomal escape of nanomedicines [55]. Finally, the incorporation of photosensitizers able to produce radical oxidative species (ROS) upon exposure to certain wavelengths of light induces the controlled endosomal disruption under light exposure [56]. Double targeting

• the power of the CPP for an effective internalization and an endosomal escape to the cytosol (Figure 5). This methodology has been applied by using a combination of RGD-type or NGR-type peptide specific for neovascular tissues with R8 (eight units of arginine) or R4 (four units of arginine) CPP

In vitro interaction of colloidal nanoparticles with mammalian cells: What have we learned thus far?

• Moritz Nazarenus,
• Qian Zhang,
• Mahmoud G. Soliman,
• Pablo del Pino,
• Beatriz Pelaz,
• Susana Carregal-Romero,
• Joanna Rejman,
• Barbara Rothen-Rutishauser,
• Martin J. D. Clift,
• Reinhard Zellner,
• G. Ulrich Nienhaus,
• James B. Delehanty,
• Igor L. Medintz and
• Wolfgang J. Parak

Beilstein J. Nanotechnol. 2014, 5, 1477–1490, doi:10.3762/bjnano.5.161

• (cf. Figure 4). Inside those intracellular vesicles the NPs are in an environment (acidic pH, enzymes) completely different from that in the cytosol (cf. Figure 5). Endocytosis and the endosomal escape dilemma have to be taken into account in particular concerning the delivery applications of NPs, in

• modify their properties. The translocation of the NPs from these vesicles to the cytosol is a current challenge, which is referred to as endosomal escape dilemma. Uptake studies best should involve a quantitative distribution analysis. While endocytotic uptake of NPs has been extensively investigated