Traditional synthetic polymer carriers are restricted due to microplastic pollution, whereas, natural polymer materials have gained widespread use as wall materials for carriers due to their biodegradability, availability, ease of modification, and biocompatibility. The mechanical properties of carriers are particularly crucial for formulation design, storage stability, and practical performance. However, there is currently a lack of reviews on the mechanical properties of natural polymer-based carriers (NPC). This paper delves into the mechanical properties of NPC from five aspects: First, natural polymer wall materials are classified into polysaccharide-based, protein-based, lipid-based, and composite materials, focusing on polysaccharide-dominated systems, and the mechanical properties of NPC constructed from materials of different origins are summarized. Second, various preparation techniques for NPC are introduced, summarizing the mechanical properties of carriers constructed by each method. The paper then examines regulation strategies of the mechanical properties of NPC, including modification techniques, encapsulated substances, morphology, and particle size. Next, methods for characterizing mechanical properties of NPC are introduced. Finally, there is a summary of the progress of NPCs with different mechanical properties in fields, highlighting the challenges faced and proposing future research directions. This review links mechanical optimization to performance, bridging research and applications with eco-friendly NPC strategies.

Targeting nanotechnology has emerged as a promising approach in drug delivery systems, offering enhanced therapeutic efficacy and reduced side effects. The physicochemical properties of nanocarriers largely influence the interaction of the nanocarrier within the body and its intended targets. Factors such as size, shape, surface charge, and elasticity play crucial roles in determining the nanocarrier's ability to navigate biological barriers, evade the immune system, and selectively accumulate at the target site. Recent advancements in nanotechnology have led to the development of newer nanocarriers with improved targeting capabilities. These innovative designs incorporate smart materials that respond to specific stimuli, such as pH changes or enzyme activity, allowing precise control over drug release. The understanding and optimization of these physicochemical properties are essential for designing more effective and efficient targeted drug delivery systems, potentially revolutionizing the treatment of various diseases, particularly in cancer therapy. Additionally, surface modifications with ligands further enhance the specificity of nanocarrier-target interactions. The intersection of protein corona, tumor microenvironment, biological barriers, and nanoparticles' physicochemical properties offers several challenges in cancer-targeted treatment. Moreover, we discussed the current situation and remaining challenges of various targeting methods with receptors, nanocarrier systems targeting carcinoma, which could facilitate the advancement of targeted nanodrug delivery systems in the future. This review synthesizes advances in nanocarriers design from 2015 to 2025, focusing on cancer-specific targeting, offering a thorough analysis of all critical parameters that need to be meticulously studied to select the most suitable nanocarrier approaches for successful clinical translation.

The chemical conjugation of poly(ethylene glycol) (PEG) to therapeutic agents, known as PEGylation, is a well-established strategy for enhancing drug solubility, chemical stability, and pharmacokinetics. Here, we report on a class of supramolecular polymeric prodrugs by utilizing oligo(ethylene glycol) (OEG) to modify the hydrophobic anticancer drug camptothecin (CPT). These OEGylated prodrugs, despite their low molecular weight, spontaneously self-assemble into therapeutic supramolecular polymers (SPs) with a tubular morphology, featuring a dense OEG coating on the surface. By designing biodegradable linkers with varying chemical stabilities, we investigated how the release kinetics of CPT influence the in vitro and in vivo performance of these SPs. Our findings demonstrate that self-assembling prodrugs (SAPDs) with a self-immolative disulfanyl-ethyl carbonate (etcSS) linker exhibit a faster drug release rate than those with a reducible disulfanyl butyrate (buSS) linker, leading to higher potency and significantly improved antitumor efficacy. Notably, two stable tubular SPs, Tubustecan (TT) 1E and TT 7E, outperformed irinotecan─a clinically approved CPT prodrug─in a colon cancer model, achieving enhanced tumor growth inhibition and prolonged animal survival. These results highlight the potential of supramolecular OEGylation as an important strategy for engineering drug-based supramolecular polymers and underscore the critical role of chemical stability vs supramolecular stability in optimizing supramolecular prodrug design.

Cannabinoids and terpenes, key bioactive components of cannabis, are increasingly studied for their individual and combined contributions to the therapeutic potential of cannabis-based treatments, with ongoing research exploring their distinct and interactive effects. This study aimed to encapsulate cannabigerolic acid (CBGA) in poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles (PEG-PLGA NPs) and investigate the effects of combining CBGA NPs with cannabis-derived terpene-loaded NPs (myrcene [MC], nerolidol [NL], and caryophyllene [CPh]) for potential applications in pain management. CBGA NPs (152 nm) and terpene-loaded NPs (233-297 nm) were prepared via nanoprecipitation and emulsion-solvent evaporation, respectively, exhibiting a polydispersity index < 0.3 and negative zeta potentials (-23 to -26 mV). Encapsulation efficiency was 98.6 % for CBGA and 13-33 % for terpenes. CBGA release followed a biphasic profile, with ∼ 20 % released within 4 h and sustained release over 72 h. In vitro evaluation used HEK293 cells expressing the nociceptive transient receptor potential vanilloid-1 (TRPV1) channel, a key mediator of pain perception. TRPV1 activation was assessed via calcium influx kinetics (Fluo-4 indicator). The EC50 values were 23.8 µg/mL (CBGA NPs), 8.0 µg/mL (MC NPs), 6.7 µg/mL (NL NPs), and 13.3 µg/mL (CPh NPs). Combinatorial treatments of CBGA NPs with terpene NPs at their respective EC50 concentrations revealed significantly enhanced calcium influx compared to individual NPs, with the strongest interaction observed for CBGA/NL and moderate effects for CBGA/MC. Fluorescence imaging further corroborated these findings. These results suggest that combining CBGA NPs with terpene-loaded NPs could potentiate pain-relief efficacy, offering a promising strategy for advanced therapeutic formulations.

Doxorubicin (Dox) is a potent anticancer agent; however, its therapeutic efficacy is constrained by a narrow therapeutic index, resulting in nonselective cardiotoxicity and nephrotoxicity. To improve its specificity and therapeutic efficacy, multivalent targeting strategies are being developed.

A chimeric polypeptide consisting of an elastin-like polypeptides (ELP) copolymer with a repeating IL-4 receptor-specific targeting peptide, AP-1, and a (GGCGSCGSC)2 sequence encoding 6 cysteine residues (C6) at the carboxyl-terminus for Dox conjugation was designed. Several AP1-ELPs of varying molecular sizes and structures, ranging from unimers to micelle-forming polymers, were characterized to evaluate their influence on Dox delivery and tumor inhibition.

Conjugating Dox to the C6 via an acid-labile linker induced self-assembly into micelle-like structures at body temperature. The size of these multivalent constructs significantly influenced their tumor penetration and overall therapeutic outcomes. High molecular weight, micelle-forming AP1-ELP constructs demonstrated faster tumor entry and enhanced inhibition compared to lower molecular weight linear AP1-ELPs. Tumor uptake of Dox was five times greater than that of free drug and twice that of low molecular weight, linear AP1-ELPs. Furthermore, systemic administration of these high molecular weight constructs effectively inhibited tumor growth in breast carcinoma xenograft models without inducing specific organ toxicity.

Outperforming free Dox, high molecular weight micelle-forming AP1-ELP constructs achieve superior tumor targeting and efficacy with minimal toxicity, highlighting their potential as safer and more promising carriers for targeted drug delivery.

Over past decades, a wide range of nanomaterials have been synthesized and exploited to augment the efficacy and biocompatibility of disease theranostics and nanomedicine. The unique physicochemical properties of nanomaterials, such as high specific surface area, tunable size and shape, and versatile surface chemistry, enable the controlled modulation of nanomaterial-biosystem interactions and, consequently, more precise interventions, particularly at the cellular level. The selective modulation of nanomaterial-cell interactions can be leveraged to regulate cellular internalization, intracellular trafficking and localization, and cellular clearance of nanomaterials to enhance the disease therapeutic efficacy and minimize potential cytotoxicity. Herein, we provide an overview of our recent understanding of the journey and modes of action of therapeutic nanomaterials in cells. Specifically, we highlight the various pathways of cellular internalization, trafficking, and excretion of these nanomaterials. The different modes of action of therapeutic nanomaterials, especially controlled release and delivery, photothermal and photodynamic effects, and immunomodulation, are also discussed. We conclude our review by offering some perspectives on the current challenges and potential opportunities in this field.

The field of nanomedicine has been fruitful in creating novel drug delivery ideas to battle hematologic cancers. However, one persistent barrier to efficient nanoparticle treatment is phagocytic uptake or the clearance of nanoparticles by immune cells. To prevent this immune uptake, scientists have utilized biomimicry, the emulation of natural structures for engineered applications, to create particles that are able to remain unrecognized by immune cells. This method aims to improve the overall circulation time of nanoparticles by decreasing the amount of particles filtered out of the blood. It can even lead to homotypic cancer cell targeting, decreasing cancer cell vitality. This review summarizes recent in vivo and in vitro studies to prove that biomimetic cargo delivery is a unique and tenable way of increasing survival outcomes in patients with hematologic cancers.

Aquatic organisms are inevitably exposed to metallic nanoparticles (NPs) in natural environments, leading to potential harm, ecological disruption, and environmental pollution concerns. Importantly, the size of NPs plays a critical role in influencing their uptake by these organisms. Utilizing mass cytometry, we investigated the internalization characteristics of different-sized gold NPs (AuNPs) in an unicellular ciliate Tetrahymena thermophila, under a low exposure concentration of 1 ngmL-1. This investigation, conducted at both the population and single-cell levels, revealed that the size of AuNPs significantly affected their uptake by T. thermophila cells. The average mass of intracellular AuNPs peaked at 0.5 h and subsequently decreased, attributed to the efflux of AuNPs or cell proliferation. Larger AuNPs resulted in a lower average intracellular AuNPs mass and a smaller proportion of T. thermophila cells accumulating AuNPs (Au-positive (AuP) T. thermophila). However, when exposed to larger AuNPs, the AuPT. thermophila cells had a higher AuNPs mass and volumetric concentration factors compared to their exposure to smaller AuNPs. After exposure, while most AuPT. thermophila cells had intracellular Au content below 2.41 × 10-15 g cell-1, the small groups of T. thermophila cells that accumulated higher mass of AuNPs may be the ones more susceptible to the effects of AuNPs exposure. Additionally, we developed a three-dimensional fitting surface model to depict the relationship among exposure time, AuNP size, and intracellular AuNPs mass in individual T. thermophila cells. This study enhances our understanding of size-specific NPs accumulation in unicellular organisms and provides valuable insights for ecological risk assessment of different sized NPs.

Herein an easy preparation method for anisotropic nanoparticles (NPs) is reported, in which the orientation of the composed molecules aligns at a certain direction in the particle, using a conventional reprecipitation method in combination with a microwave irradiation. The size, shape, and anisotropy of NPs strongly affect several physical properties and thus their regulation is essential for applications. Although some successful examples of size and shape regulation of NPs have been reported recently, the regulation of anisotropy is still challenging. In this study, NPs of azobenzene liquid crystalline polymer (LCP) using a conventional reprecipitation method, and then irradiation with microwave are introduced. With this treatment, the phase transition from the glassy phase to the smectic phase of azobenzene LCP is induced and the azobenzene groups are oriented at a certain direction. The anisotropy of NPs is confirmed by preparing fluorescent dye-doped NPs. The prepared NPs exhibit polarization dependence of signals in the fluorescence image, which originates from the uniaxial orientation of molecules inside NPs. Furthermore, the anisotropy of NPs can be reversibly controlled with external light or heat stimuli.

Deformability has been recognized as a prime important characteristic influencing cellular uptake. But little is known about whether it controls cell-nanoparticle interfaces driven out of equilibrium. Here, we report on soft elastic active nanoparticles whose deformability due to the rigidity regulates the nonequilibrium interaction and dynamics in their endocytosis process. Simulations demonstrate a definitely nonmonotonic feature for the dependence of uptake efficiency on nanoparticle rigidity, in striking contrast to their passive counterpart. There exists a minimum activity for certain cellular uptake, which turns to a larger rigidity for a more vertical orientation of the nanoparticle. We analyze these results by developing analytical theories that reveal the physical origin of various energetic contributions and dissipations governed by the dynamic interplay between nanoparticle deformability and activity. Altogether, the present findings provide new insights into the nonequilibrium physics at cellular interfaces and might be of immediate interest to designing soft systems for the desired biomedical applications.

Biological nanoparticles, particularly rod-shaped plant viruses, have emerged as promising candidates for various biomedical applications. This review focuses on the morphological characteristics and modification strategies of rod-shaped plant viruses such as tobacco mosaic virus, potato virus X, and papaya mosaic virus. These viruses offer versatile modification approaches, including chemical, genetic, and bio-modifications, as well as aspect ratio regulation. Their applications in drug delivery, antibacterial treatments, RNA delivery, bioimaging, and immune modulation are extensively discussed. Rod-shaped plant viruses exhibit unique advantages, such as uniformity in size and molecular weight, excellent biocompatibility, diverse modifiability and inherent immunogenicity, making them highly suitable for biomedical applications. However, challenges remain in their clinical translation. This review aims to provide insights into the potential of rod-shaped plant viruses as biological nanoparticles and stimulate further research in the field of virus-based biomaterials, which may lead to innovative solutions in drug delivery, immune-related therapies and vaccine development.

The influence of selenium (Se) nanoparticles in the form of rods (SeNrs) and spheres (SeSps), synthesized by laser ablation, on the structural and functional properties of human blood erythrocytes and neutrophils was studied for anticancer activity in vitro. SeNrs and SeSps do not have cytotoxicity towards neutrophils and do not cause hemolysis. The elastic modulus and resistance of erythrocytes to HOCl-induced hemolysis increased after binding of Se nanoparticles to the plasma membrane. The interaction of Se nanoparticles with neutrophils is accompanied by their actin-dependent macropinocytosis, triggering intracellular signaling processes leading to the assembly and activation of NADPH oxidase. Comparative analysis of the effects of SeNrs and SeSps on cells showed that they have similar effects. This may be due to the fact that SeNrs interact with the cell surface with their end faces, and, therefore, have the same initial contact with the plasma membrane as SeSps. However, SeSps and SeNrs showed chronic cytotoxicity after 48 h incubation, indicating the need to find ways to reduce their toxicity further. Further use of Se nanoparticles in anisotropic form in biomedical research for the development of therapeutic agents seems promising.

Theranostic polymers have emerged as a versatile platform in cancer nanomedicine, integrating therapeutic and imaging functionalities to overcome challenges in oncology. Featuring diverse architectures such as linear polymers, dendrimers, star-like polymers, and bottle-brush polymers, these systems enable tumor-targeted drug delivery, real-time imaging, and controlled release. Recent advances in stimuli-responsive designs and biomimetic strategies have improved their specificity, stability, and adaptability, outperforming conventional nanocarriers. This review summarizes the design, synthesis, and biomedical applications of theranostic polymers, focusing on their potential to address tumor heterogeneity and biological barriers. The challenges of biocompatibility, immunogenicity, and clinical translation are discussed, with a perspective toward future developments in precision medicine and imaging-guided cancer therapy.

Nanovaccines, as a new generation of vaccines, have garnered significant interest due to their exceptional potential in enhancing disease prevention and treatment. Their unique features, such as high stability, antigens protection, prolonged retention, and targeted delivery to lymph nodes, immune cells, and tumors, set them apart as promising candidates in the field of immunotherapy. Polymers, with their superior degradability, capacity to mimic pathogen characteristics, and surface functionality that facilitates modifications, serve as ideal carriers for vaccine components. Polymer-based self-adjuvanted nanovaccines have the remarkable ability to augment immune responses. The inherent adjuvant-like properties of polymers themselves offer a pathway toward more efficient exploitation of nanomaterials and the optimization of nanovaccines. This review article aims to summarize the categorization of polymers and elucidate their mechanisms of action as adjuvants. Additionally, it delves into the advantages and limitations of polymer-based self-adjuvanted nanovaccines in disease management and prevention, providing valuable insights for their design and application. This comprehensive analysis could contribute to the development of more effective and tailored nanovaccines for a wide range of diseases.

With the high production and use of plastic products, a large amount of microplastics (MPs) is generated by degradation, which causes environmental pollution. MPs are particles with a diameter <5 mm; further degradation of MPs produces nano‑plastics (NPs), which could further increase the damage to cells when entering the human body. Therefore, the present review summarizes the effect of MP and NP deposition on the human gastrointestinal tract and the underlying injury mechanism of oxidative stress, inflammation and apoptosis, as well as the potential mechanism of glucose and liver lipid metabolism disorder. The present review provides a theoretical basis for research on the mechanisms of MPs in gastrointestinal injury and liver metabolism disorder. Further studies are needed for prevention and treatment of gastrointestinal diseases caused by MPs and NPs.

The treatment and management of kidney diseases pose a significant global burden. Due to the presence of blood circulation barriers and glomerular filtration barriers, drug therapy for kidney diseases faces challenges such as poor renal targeting, short half-life, and severe systemic side effects, severely hindering therapeutic progress. Therefore, the research and development of kidney-targeted therapeutic agents is of great clinical significance. In recent years, the application of nanotechnology in the field of nephrology has shown potential for revolutionizing the diagnosis and treatment of kidney diseases. Carefully designed nanomaterials can exhibit optimal biological characteristics, influencing various aspects such as circulation, retention, targeting, and excretion. Rationally designing and modifying nanomaterials based on the anatomical structure and pathophysiological environment of the kidney to achieve highly specific kidney-targeted nanomaterials or nanodrug delivery systems is both feasible and promising. Based on the targeted therapy of kidney diseases, this review discusses the advantages and limitations of current nanomedicine in the targeted therapy of kidney diseases, and summarizes the application and challenges of current renal active/passive targeting strategies, in order to further promote the development of kidney-targeted nanomedicine through a preliminary summary of previous studies and future prospects.

Nanoengineered encapsulation presents a promising strategy for targeted drug delivery to specific regions in the body. While polyelectrolyte-based biodegradable microcapsules can achieve highly localised drug release in tissues and cell cultures, delivering drugs to intracellular sites in the brain remains a significant challenge. In this study, we utilized advanced imaging techniques, both in vitro and in vivo, to investigate whether brain neurons can internalise polyelectrolyte-based microcapsules designed for drug delivery. High-resolution live-cell imaging revealed that differentiating N2A cells actively internalise microcapsules, often incorporating multiple capsules per cell. Likewise, primary hippocampal and cortical neurons were observed to effectively internalise polymeric microcapsules. In the intact brain, multiplexed two-photon excitation imaging in vivo confirmed the internalisation of microcapsules by cortical neurons following delivery to the somatosensory brain region. This internalisation was time-dependent, correlated with particle size and mediated by a macropinocytosis mechanism that appears to bypass lysosomal formation. Importantly, the presence of internalised microcapsules did not impair neuronal function, as neurons maintained normal firing activity and action potential characteristics. Furthermore, no adverse effects were observed after a week of microcapsule presence in the mouse brain. Our findings indicate that polymeric microcapsules are effective and safe carriers for intracellular drug delivery to brain neurons, providing a targeted approach with potential therapeutic applications.

The practical benefits and therapeutic potential of tumor vaccines in immunotherapy have drawn significant attention in the field of cancer treatment. Among the available vaccines, nanovaccines that utilize nanoparticles as carriers or adjuvants have demonstrated considerable effectiveness in combating cancer. Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN), a common adjuvant in tumor nanovaccines, activates both humoral and cellular immunity by recognizing toll-like receptor 9 (TLR9), thereby aiding in the prevention and treatment of cancer. Metal nanoparticles hold great promise in tumor immunotherapy due to their adjustable size, surface functionalization, ability to regulate innate immunity, and capacity for controlled delivery of antigens or immunomodulators. Consequently, composite nanoadjuvants, formed by combining metal nanoparticles with CpG ODNs, can be customized to meet the specific performance requirements of different application scenarios, effectively overcoming the limitations of conventional immunotherapy approaches. This review provides a comprehensive analysis of the critical role of metal-CpG composite nanoadjuvants in advancing vaccine adjuvants for cancer therapy and prevention, highlighting their efficacy in preclinical settings.

Computed tomography (CT) is widely used all over the world, and the detection rate of early lung adenocarcinoma is increasing. Minimally invasive thoracic surgery (MITS) has emerged as the preferred surgical approach for lung adenocarcinoma, but identifying small lung adenocarcinomas is difficult. Therefore, there is a need for a non-invasive, convenient and efficient way to localize lung adenocarcinomas.

A targeted gold nanocluster for intraoperative fluorescence imaging by intratracheal delivery has been designed. Au-GSH-anti Napsin A nanoclusters (NapA-AuNCs) were synthesized, and their physicochemical properties and optical properties were characterized. Target effect, cytotoxicity and fluorescence time curve of NapA-AuNCs, were tested in vivo and in vitro, and intratracheal delivery was also carried.

NapA-AuNCs targeting lung adenocarcinoma with red fluorescence and good mucus penetration were synthesized, which had the targeting property of A549 and lung adenocarcinoma tissue, and also had very low toxicity to normal lung epithelial cells and organs. Intracheal delivery involves faster imaging of lung adenocarcinoma and less accumulation of other organs than intravenous administration.

NapA-AuNCs targeting lung adenocarcinoma were successfully conjugated, and intratracheal delivery is a safe, effective for lung adenocarcinoma intraoperative localization.

The DNA repair system relies on the coordinated action of multiple enzymes to maintain genomic stability, with apurinic/apyrimidinic endonuclease 1 (APE1) and flap endonuclease 1 (FEN1) playing pivotal roles in the long-patch base excision repair (LP-BER) pathway. Elevated levels of APE1 and FEN1 have been associated with tumor progression and resistance to therapy, making them key biomarkers for cancer diagnosis and treatment monitoring. Here, we present a sequentially activated AND-logic DNA sensor (D-AF) for the correlated imaging of APE1 and FEN1 in living cells. The sensor operates through a sequential process: APE1 first recognizes and cleaves an apurinic site, initiating structural changes that enable FEN1 to cleave a 5' flap, resulting in restored fluorescence. We demonstrate the use of the D-AF-based nanosensor for in situ imaging of APE1 and FEN1 activities in cancer cells and for monitoring of enzyme dynamics during chemotherapy. This platform offers a valuable tool for investigating DNA repair mechanisms and their roles in cancer diagnosis and treatment.

Peptide-based self-assembled nanosystems show great promise as non-viral gene and siRNA delivery vectors. In the current study, we designed and functionalized nanofibers for the delivery of siRNA, targeting and silencing EGFR gene overexpressed in triple-negative breast cancer. The nanofiber-mediated siRNA delivery was characterized in terms of zeta potential, morphology, and structural stability by circular dichroism spectroscopy. In cytotoxicity studies, nanofibers presented high biocompatibility showing a negligible effect on cell viability both on healthy and cancer cell lines. The binding between nanofibers and EGFR-siRNA was investigated and ascertained by performing different biophysical studies. The complex siRNA:NF was stable over time, under fetal bovine serum, temperature and ionic strength effects. Moreover, nanofibers effectiveness in stabilizing and delivering an ad hoc selected siRNA for EGFR gene expression silencing was verified in a preclinical model of triple-negative breast cancer. Specifically, a significant gene knockdown was obtained with the complex siRNA:NF, that is comparable with the effect obtained by lipofectamine/siRNA transfection. This effective gene silencing derived from the successful internalization of nanofibers by cancer cells as observed by confocal microscopy. These results suggested that this peptide-based nanofiber could be an effective and safe systemic siRNA delivery system for application in biomedical areas.

Self-assembly plays a critical role in nanoparticle-based applications. However, it remains challenging to monitor the self-assembly of multi-component nanomaterials at a single-particle level, in real-time, with high throughput, and in a model-independent manner. Here, multi-color fluorescence microscopy is applied to track the assembly of both liposomes and mRNA simultaneously in clinical mRNA-based cancer immunotherapy. Imaging reveals that the assembly occurs in discrete steps: initially, RNA adsorbs onto the liposomes; then, the RNA-coated liposomes cluster into heterogeneous structures ranging from sub-micrometer to tens of micrometers. The clustering process is consistent with a Smoluchowski model with a Brownian diffusion kernel. The transition between the two steps of assembly is determined by the orientation of RNA-mediated interactions. Given the facile application of this approach and the ubiquity of the components studied, the imaging and analysis in this work are readily applied to monitor multi-component assembly of diverse nanomaterials.

This review discusses the literature data on the synthesis, physicochemical properties, and cytotoxicity of composite nanoparticles bearing the mitochondrial protein cytochrome c (cytC), which can act as a proapoptotic mediator in addition to its main function as an electron carrier in the electron transport chain. The introduction of exogenous cytC via absorption of carrier particles, the phagocytosis of colloid particles of submicrometric size, or the receptor-mediated endocytosis of nanoparticles in cancer cells, initiates the process of apoptosis-a multistage cascade of biochemical reactions leading to complete destruction of the cells. CytC-carrier composite particles have the potential for use in the treatment of neoplasms with superficial localization: skin, mouth, stomach, colon, etc. This approach can solve the two main problems of anticancer therapy: selectivity and non-toxicity. Selectivity is based on the incapability of the normal cell to absorb (nano)particles, except for the cells of the immune system. The use of cytC as a protein that normally functions in mitochondria is harmless for the macroorganism. In this review, the factors limiting cytotoxicity and the ways to increase it are discussed from the point of view of the physicochemical properties of the cytC-carrier particles. The different techniques used for the preparation of cytC-bearing colloids and nanoparticles are discussed. Articles reporting the achievement of high cytotoxicity with each of the techniques are critically analyzed.

Heterogeneities among tumor cells significantly contribute towards cancer progression and therapeutic inefficiency. Hence, understanding the nature of cancer through liquid biopsies and isolation of circulating tumor cells (CTCs) has gained considerable interest over the years. Microfluidics has emerged as one of the most popular platforms for performing liquid biopsy applications. Various label-free and labeling techniques using microfluidic platforms have been developed, the majority of which focus on CTC isolation from normal blood cells. However, sorting and profiling of various cell phenotypes present amongst those CTCs is equally important for prognostics and development of personalized therapies. In this review, firstly, we discuss the biophysical and biochemical heterogeneities associated with tumor cells and CTCs which contribute to cancer progression. Moreover, we discuss the recently developed microfluidic platforms for sorting and profiling of tumor cells and CTCs. These techniques are broadly classified into biophysical and biochemical phenotyping methods. Biophysical methods are further classified into mechanical and electrical phenotyping. While biochemical techniques have been categorized into surface antigen expressions, metabolism, and chemotaxis-based phenotyping methods. We also shed light on clinical studies performed with these platforms over the years and conclude with an outlook for the future development in this field.

The immune system safeguards as primary defense by recognizing nanomaterials and maintaining homeostasis, gaining a deeper understanding of these interactions may change the treating paradigm of immunotherapy. Here, we adopted copper as the principal component of nanoparticles (NPs), given its features of coordination with different benezenecarboxylate ligands to form metal-organic frameworks and complexes with distinct morphologies. As a result, four types of shape-tunable copper-coordinated NPs (CuCNPs) are developed: cuboctahedron, needle, octahedron, and plate NPs. Biocompatibility of CuCNPs varies across different cell lines (RAW264.7, THP-1, HEK 293 and HeLa) in a shape-dependent manner, with needle-shaped CuCNPs showing pronounced cytotoxicity (IC50:104.3 μg mL-1 at 24 h). Among different shapes, a notable increase of 8.47% in the CD206+ subpopulations is observed in needle-shaped CuCNPs, followed by 77% enhancement at 48 h. Overall, this study underscores the shape-dependent immune-regulatory effects of CuCNPs and sheds light on the rational design of nanoscale metal complexes for potential immunotherapy.

Bio-nano interactions have been extensively explored in nanomedicine to develop selective delivery strategies and reduce systemic toxicity. To enhance the delivery of nanocarriers to cancer cells and improve the therapeutic efficiency, different nanomaterials have been developed. However, the limited clinical translation of nanoparticle-based therapies, largely due to issues associated with poor targeting, requires a deeper understanding of the biological phenomena underlying cell-nanoparticle interactions. In this context, we investigate the molecular and cellular mechanobiology parameters that control such interactions. We demonstrate that the pharmacological inhibition or the genetic ablation of the key mechanosensitive component of the Hippo pathway, i.e., yes-associated protein, enhances nanoparticle internalization by 1.5-fold. Importantly, this phenomenon occurs independently of nanoparticle properties, such as size, or cell properties such as surface area and stiffness. Our study reveals that the internalization of nanoparticles in target cells can be controlled by modulating cell mechanosensing pathways, potentially enhancing nanotherapy specificity.

Under the concept of "one airway, one disease", upper and lower airway inflammatory diseases share similar pathogenic mechanisms and are collectively referred to as airway inflammatory diseases. With industrial development and environmental changes, the incidence of these diseases has gradually increased. Traditional treatments, including glucocorticoids, antihistamines, and bronchodilators, have alleviated much of the discomfort experienced by patients. However, conventional drug delivery routes have inherent flaws, such as significant side effects, irritation of the respiratory mucosa, and issues related to drug deactivation. In recent years, nanomaterials have emerged as excellent carriers for drug delivery and are being increasingly utilized in the treatment of airway inflammatory diseases. These materials not only optimize the delivery of traditional medications but also facilitate the administration of various new drugs that target novel pathways, thereby enhancing the treatment outcomes of inflammatory diseases. This study reviews the latest research on nano-drug delivery systems used in the treatment of airway inflammatory diseases, covering traditional drugs, immunotherapy drugs, antimicrobial drugs, plant-derived drugs, and RNA drugs. The challenges involved in developing nano-delivery systems for these diseases are discussed, along with a future outlook. This review offers new insights that researchers can utilize to advance further research into the clinical application of nano-drug delivery systems for treating airway inflammatory diseases.

Psoriasis seriously affects the physical and mental health of patients. Rocaglamide (RocA), derived from Aglaia odorata, exhibits potent pharmacological activities. Although its efficacy in psoriasis is unclear, RocA could be a promising therapeutic drug. In this work, RocA showed a good therapeutic effect in psoriasis mice induced by imiquimod, and subsequent TMT-based proteomics analysis verified that the effect of RocA was related to IL-1 family cytokines. Furthermore, a RocA-loaded liposome (RocA@Lipo) was developed and encapsulated in the tip-layer of microneedles (MNs) to construct a MN-based nano drug delivery system (RocA@Lipo-MNs). In vitro HaCaT cell assays demonstrated that RocA@Lipo enhanced the cytotoxicity and cell uptake of RocA. In vivo, RocA@Lipo-MNs outperformed other RocA formulations in inhibiting psoriasis epidermal thickening and spleen enlargement. Immunohistochemical, ELISA, western blot, and PCR experiments further proved that RocA@Lipo-MNs could inhibit neutrophil infiltration in the skin, revealing that the anti-psoriasis mechanism of RocA was deemed to inhibit the binding of IL-1α and IL-1R1 to regulate the activation of MAPK and NF-κB pathways. Thus, the production of inflammatory factors and neutrophil chemokines was reduced, which was associated with apoptosis inhibition. Importantly, RocA@Lipo-MNs significantly improved the transdermal properties of RocA and exhibited good skin and blood safety. This work provides new ideas for the clinical application of RocA and the treatment options for psoriasis.

Designing molecules for multivalent targeting of specific disease markers can enhance binding stability which is critical in molecular imaging and targeted therapy. Through rational molecular design, the nanostructures formed by self-assembly of targeting peptides are expected to achieve multivalent targeting by increasing the density of recognition ligands. However, the balance between targeting peptide self-assembly and molecular recognition remains elusive. In this study, we designed a targeting-peptide-based imaging probe system TAP which consist of the signal unit, the recognition motif, the assembly motif and a Pro-leverage. It is verified that TAP could specifically binds to PD-L1-positive tumor cells in a multivalent manner to produce biological effects, and could also be combined with imaging probes through unique self-assembly strategies. By the balance between the peptide self-assembly and targeting recognition, the specificity and stability can be improved while the accumulation capacity of the probes at the tumor site can be greatly enhanced compared with the conventional strategy, thus reducing side effects, providing an effective tool for diagnostic and therapeutic integration of tumors.

The therapeutic messenger RNA strategies, such as those using small interfering RNAs, take several advantages (versatility, efficiency and selectivity) over plasmid DNA-based strategies. However, the challenge remains to find nanovectors capable of properly loading the genetic material, transporting it through troublesome environments, like a tumoral site, and delivering it into the cytoplasm of target cells. Here, lipid nanoparticles, consisting of a gemini cationic/neutral helper lipid mixture, are proposed as siRNA nanovector. Cells from cervical and brain cancer overexpressing the green fluorescent protein (GFP) were chosen to analyse the biological response as well as the efficiency and safety of the siRNA-loaded nanovector according to the cell phenotype. Flow cytometry and epifluorescence or confocal microscopy were used to follow the gene knockdown in these overexpressed cells. The effect of the nanovector on cellular proliferation was evaluated with cytotoxicity assays while their potential oxidative stress generation was determined by quantifying the generation of reactive oxygen species. To explore the mechanism of cellular uptake, different inhibitors of endocytic pathways were used during incubation with cells. Finally, nanovectors were incubated in 3D-grown cells (spheroids) to see whether they can penetrate the complex tumoral microenvironments, their efficiency to knockdown GFP expression being monitored by confocal microscopy.

Encapsulating peptide-stabilized gold nanoclusters (AuNCs) with thiolated hyaluronic acid (HA-SH) and selectively adding cysteine to the peptide sequence increased their photoluminescence. We found that peptide compositions with cysteine in the middle emitted the most. RCR-stabilized AuNCs can be purified using size-exclusion chromatography to characterize their optical characteristics, chemical composition, and possible structure. Our findings show that RCR-stabilized AuNCs have a unique chemical structure, microsecond photoluminescence lifetime, good quantum yield, and near-infrared emission peak. Due to Au-S bonding and electrostatic interactions, RCR-stabilized AuNCs were encapsulated with HA-SH to create nanocomposites. HA-SH-AuNCs had a longer emission peak, greater particle size, and better photostability than RCR-stabilized AuNCs. HAase break down HA in HA-SH-AuNCs, changing their structure and size. Thus, centrifugation makes it easier to separate HA-SH-AuNCs from HAase-digested ones. Similar to earlier sensors, HA-SH-AuNCs have great sensitivity and selectivity for HAase, with a linear range of 0.5-6.0 U/mL and a detection limit of 0.39 U/mL. They were useful for urine HAase determination, with spike recovery of 103 % to 107 %. HA-SH-AuNCs further served as a platform for targeted imaging of CD44 receptor-expressing cancer cells, demonstrating bioimaging and clinical diagnostic potential.

Cancer immunotherapy, which leverages immune system components to treat malignancies, has emerged as a cornerstone of contemporary therapeutic strategies. Yet, critical concerns about the efficacy and safety of cancer immunotherapies remain formidable. Nanotechnology, especially polymeric nanoparticles (PNPs), offers unparalleled flexibility in manipulation-from the chemical composition and physical properties to the precision control of nanoassemblies. PNPs provide an optimal platform to amplify the potency and minimize systematic toxicity in a broad spectrum of immunotherapeutic modalities. In this comprehensive review, the basics of polymer chemistry, and state-of-the-art designs of PNPs from a physicochemical standpoint for cancer immunotherapy, encompassing therapeutic cancer vaccines, in situ vaccination, adoptive T-cell therapies, tumor-infiltrating immune cell-targeted therapies, therapeutic antibodies, and cytokine therapies are delineated. Each immunotherapy necessitates distinctively tailored design strategies in polymeric nanoplatforms. The extensive applications of PNPs, and investigation of their mechanisms of action for enhanced efficacy are particularly focused on. The safety profiles of PNPs and clinical research progress are discussed. Additionally, forthcoming developments and emergent trends of polymeric nano-immunotherapeutics poised to transform cancer treatment paradigms into clinics are explored.

Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery. In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake. Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions. In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.

Plant virus-like particles (pVLPs) present distinct research advantages, including cost-effective production and scalability through plant-based systems, making them a promising yet underutilized alternative to traditional VLPs. Human exposure to plant viruses through diet for millions of years supports their biocompatibility and safety, making them suitable for biomedical applications. This review offers a practical guide to selecting pVLPs based on critical design factors. It begins by examining how pVLP size and shape influence cellular interactions, such as uptake, biodistribution, and clearance, key for effective drug delivery and vaccine development. We also explore how surface charge affects VLP-cell interactions, impacting binding and internalization, and discuss the benefits of surface modifications to enhance targeting and stability. Additional considerations include host range and biosafety, ensuring safe, effective pVLP applications in clinical and environmental contexts. The scalability of pVLP production across different expression systems is also reviewed, noting challenges and opportunities in large-scale manufacturing. Concluding with future perspectives, the review highlights the innovation potential of pVLPs in vaccine development, targeted therapies, and diagnostics, positioning them as valuable tools in biotechnology and medicine. This guide provides a foundation for selecting optimal pVLPs across diverse applications.

Human lens epithelial cells (hLECs) are critical for lens transparency, and their aberrant metabolic activity and gene expression can lead to cataract. Intracellular delivery to hLECs, especially to sub-cellular organelles (e.g., mitochondrion and nucleus), is a key step in engineering cells for cell- and gene- based therapies. Despite a broad variety of nano- and microparticles can enter cells, their spatial characteristics relevant to cellular uptake and localization remains elusive. To investigate cellular internalization of nanostructures in hLECs, herein, DNA nanotechnology was exploited to precisely fabricate four distinct, mass-controlled DNA-origami nanostructures (DONs) through computer-aided design. Ensembled DONs included the rods, ring, triangle, and octahedron with defined geometric parameters of accessible surface area, effective volume, compactness, aspect ratio, size and vertex number. Atomic force microscopy and agarose gel electrophoresis showed that four DONs self-assembled within 3.5h with up to 59% yield and exhibited structural intactness in cell culture medium for 4 h. Flow cytometry analysis of four Cy5-labelled DONs in hLECs HLE-B3 found time-dependent cellular uptake over 2 h, among which the octahedron and triangle had higher cellular accumulation than the rod and ring. More importantly, the vertex number among other geometric parameters was positively correlated with cellular entry. Confocal images further revealed that four DONs had preferential localization at mitochondria to nucleus at 2 h in HLE-B3 cells, and the degree of their biodistribution varied among DONs as evidenced by Manders' correlation coefficient. This study demonstrates the DONs dependent cellular uptake and intracellular compartment localization in hLECs, heralding the future design of structure-modulating delivery of nanomedicine for ocular therapy.

Gold nanoparticles (AuNPs) have unique properties that promise new and improved methods for targeting cancer treatment and diagnosis. However, despite their relatively high biocompatibility, AuNPs can negatively affect cell viability. Research indicates that the interactions with the plasma membrane and cellular uptake of AuNPs depend significantly on size, shape, and surface modifications.

We evaluated the use of human lymphocyte primary culture as a model for assessing the to-xicity of AuNPs in proliferating cells. We compared the toxicity of rod-shaped, PEGylated AuNPs (gold nanorods, AuNRs) of two different sizes and gold nanospheres (AuNSs).

Our results show that at high concentrations, both AuNSs and AuNRs negatively affect the viability of activated human lymphocytes in vitro. The cytotoxic effect varies with size and concentration, with larger AuNRs (approx. 22 × 50 nm) being more toxic than smaller ones (approx. 20 × 40 nm) and 15 nm AuNSs exhibiting the lowest toxicity.

Our results confirm that the application of AuNPs in cancer the-rapy and diagnostics must be accompanied by a thorough cytotoxicity assessment. Despite certain limitations, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction test for viability assessment of proliferating cells proves to be a simple and cost-effective method useful in nanoparticle toxicity studies.

Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field, due in part to low local blood flow and poor interactions between drug carriers and bone material. Here we report bone-targeting ionizable lipids incorporating a piperazine backbone and bisphosphate moieties, which bind tightly with hydroxyapatite ([Ca5(PO4)3OH]), a key component of mineralized tissues. These lipids demonstrate biocompatibility and low toxicity in both vitro and in vivo studies. LNP formulated with these lipids facilitated efficient cellular transfection and improved binding to hydroxyapatite in vitro, and targeted delivery to the bone microenvironment in vivo following systemic administration. Overall, our findings demonstrate the critical role of the piperazine backbone in a novel ionizable lipid, which incorporates a bisphosphonate group to enable efficient bone-targeted delivery, highlighting the potential of rational design of ionizable lipids for next-generation bone-targeting delivery systems.

Nanoparticles have been of significant interest in various biomedical domains such as drug delivery, gene delivery, cytotoxicity analysis, and imaging. Despite the synthesis of a variety of nanoparticles, their cellular uptake efficiency remains a substantial obstacle, with only a small fraction of delivered nanoparticles (NPs) have been reported to traverse the cell membrane within 24 h. Consequently, higher doses are often necessitated, leading to increased toxicity concerns. In this investigation, we illustrate that nanoparticles having negative Gaussian curvature demonstrate rapid and efficient internalization into cells by lowering the energy barrier for membrane bending. Specifically, three types of gold nanoparticles; gold nanorods (GNR), gold nanodogbones at pH 4 (GDB4), and gold nanodogbones at pH 6 (GDB6) were synthesized, with Gaussian curvatures of 0, -166.91, and -376.62, respectively. Cellular uptake studies conducted via ICP-OES analysis reveal that GDB6 is taken up 140% more in A549 cells and 77% more in NIH3T3 cells compared to GNR. Confocal microscopy-based uptake studies further confirm the higher uptake of GDB6 compared to GNR. Additionally, molecular simulations indicate that GDB nanoparticles exhibit a significantly larger free energy change during translocation compared to GNR, emphasizing the impact of nanoparticle shape on uptake and translocation through the membrane and validating the efficacy of negative Gaussian curvature in enhancing cellular uptake, consistent with experimental observations. Overall, our findings emphasize the importance of nanoparticle curvature modulation in maximizing cellular uptake efficiency for improved biomedical applications, providing valuable insights into the design of nanomaterials for drug delivery purposes.

The cationic surface charge critically influences the biological functions and therapeutic outcomes of the cancer nanomedicines. However, the basic correlation between the cationic group categories and their therapeutic efficacy has not been elucidated. In this study, cationic polymeric nanoparticles with amino groups (primary, tertiary, and quaternary amines) as the single variable were leveraged to investigate the various effects of amino species for enhanced antitumor chemotherapy. The nanoparticles were constructed from a series of triblock polymers with varying cationic repeating units at the hydrophilic-hydrophobic interface. Our results suggested that quaternary ammonium outperforms its primary and tertiary counterparts in destroying mitochondrial membranes to induce apoptosis, penetrating deep inside the tumor tissue, and damaging tumor vasculatures. As a result, we were able to effectively inhibit tumor growth in mice by a quaternary ammonium conjugate without causing significant toxicity. Our work demonstrated that the chemical structures played vital roles in regulating their biological functions and provided valuable information for designing cationic drug delivery systems.