MXene-Based Pressure Sensor with a Self-Healing Property for Joule Heating and Friction Sliding.

As a kind of flexible electronic device, flexible pressure sensor has attracted wide attention in medical monitoring and human-machine interaction. With the continuous deepening of research, high-sensitivity sensor is developing from single function to multi-function. However, Current multifunctional sensors lack the ability to integrate joule heating, detect sliding friction, and self-healing. Herein, a MXene/polyurethane (PU) flexible pressure sensor with a self-healing property for joule heating and friction sliding is fabricated. The MXene/PU sensitive layer with special spinosum structure is prepared by a simple spraying method. After face-to-face assembly of the sensitive layers, the MXene/PU flexible pressure sensor is obtained and showed excellent sensitivity (150.65 kPa-1), fast response/recovery speed (75.5/63.9 ms), and good stability (10 000 cycles). Based on the self-healing property of PU, the sensor also has the ability to heal after mechanical damage. In addition, the sensor realizes the joule heating function under low voltage, and has the real-time monitoring ability of sliding objects. Combined with low cost and simple manufacturing method, the multi-functional MXene/PU flexible sensor shows a wide range of application potential in human activity monitoring, thermal management, and slip recognition.

Overcoming Pharmaceutical Bottlenecks for Nucleic Acid Drug Development.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic and swift approval of two mRNA vaccines have put nucleic acid therapeutics in the spotlight of both the scientific community and the general public. Actually, in addition to mRNAs, multiple nucleic acid therapeutics have been successively commercialized over the past few years. The rapid development of nucleic acid drugs not only demonstrates their superior potency but also marks a new era of the field. Compared with conventional treatments targeting proteins rather than the root causes of diseases at the genetic level, nucleic acids are capable of achieving long-standing or even curative effects against undruggable disorders by modulating gene expression via inhibition, editing, addition, or replacement. This offers a terrific arsenal for expanding therapeutic access to diseases lacking current treatment options and developing vaccines to provide swift responses to emerging global health threats.Despite the stunning success and recent resurgence of interest in the field, the unfavorable physicochemical characteristics (i.e., the negative charge, large molecular weight, and hydrophilicity), susceptibility to nuclease degradation, off-target toxicity, and immunogenicity are a brake for moving nucleic acid therapeutics from bench to bedside. Currently, developing technologies to improve the circulation stability, targeting affinity, cellular entry, endolysosomal escape, efficacy, and safety of nucleic acid drugs still remains a major pharmaceutical bottleneck.In this Account, we outline the research efforts from our group on the development of technology platforms to overcome the pharmaceutical bottlenecks for nucleic acid therapeutics. We have engineered a variety of intelligent delivery platforms such as synthetic nanomaterials (i.e., lipid nanoparticles, polymers, and inorganic nanoparticles), physical delivery methods (i.e., electroporation), and naturally derived vehicles (i.e., extracellular vesicles), aiming at endowing nucleic acids with improved circulation stability, targeting affinity, and cellular internalization (Get in) and stimuli responsive endolysosomal escape capability (Get out). Moreover, we will discuss our progress in developing a series of modification strategies for sequence engineering of nucleic acids to endow them with enhanced nuclease resistance, translation efficiency, and potency while alleviating their off-target toxicity and immunogenicity (Sequence engineering). Integrating these technologies may promote the development of nucleic acid therapeutics with potent efficacy and improved safety (Efficacy & safety). With this Account, we hope to offer insights into rational design of cutting-edge nucleic acid therapeutic platforms. We believe that the continuing advances in nucleic acid technologies together with academic-industry collaborations in the clinic, will promise to usher in more clinically translatable nucleic acid therapeutics in the foreseeable future.

Dissolution enhancement of tadalafil by liquisolid technique.

This study aimed to enhance the dissolution of tadalafil, a poorly water-soluble drug by applying liquisolid technique. The effects of two critical formulation variables, namely drug concentration (17.5% and 35%, w/w) and excipients ratio (10, 15 and 20) on dissolution rates were investigated. Pre-compression tests, including particle size distribution, flowability determination, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and scanning electron microscopy (SEM), were carried out to investigate the mechanism of dissolution enhancement. Tadalafil liquisolid tablets were prepared and their quality control tests, dissolution study, contact angle measurement, Raman mapping, and storage stability test were performed. The results suggested that all the liquisolid tablets exhibited significantly higher dissolution rates than the conventional tablets and pure tadalafil. FT-IR spectrum reflected no drug-excipient interactions. DSC and XRD studies indicated reduction in crystallinity of tadalafil, which was further confirmed by SEM and Raman mapping outcomes. The contact angle measurement demonstrated obvious increase in wetting property. Taken together, the reduction of particle size and crystallinity, and the improvement of wettability were the main mechanisms for the enhanced dissolution rate. No significant changes were observed in drug crystallinity and dissolution behavior after storage based on XRD, SEM and dissolution results.

A method for the preparation of sustained release-coated Metoprolol Succinate pellet-containing tablets.

The purpose of this study was to develop a method to prepare Metoprolol Succinate (MS) sustained release pellets and compress them into pellet-containing tablets without losing sustained release property. The drug layered pellets were coated with Eudragit NE 30D to obtain a sustained release (SR) property. The mechanical properties and permeability of the coating film were tailored by adjusting the proportion of talc in the coating dispersion and the weight gain of the coating film. Pellets with different MS release rates were tested and then mixed together by different ratios to optimize drug release rate. The mixed pellets were compressed into tablets with cushioning excipients. The results showed that when the ratio of talc and coating material was 1:4, the coating operation could be conducted successfully without pellet conglutination and the mechanical property of the coating film was enhanced to withstand the compress force during tableting. Blending SR-coated pellets of 20% weight gain with SR-coated pellets of 40% weight gain at the ratio of 1:5 could produce a constant and desired drug release rate. The formulation and the procedure developed in the study were suitable to prepare MS pellet-containing tablets with selected SR properties.

Antegrade flexible ureteroscopy-assisted percutaneous nephrolithotomy for staghorn calculi: a prospective randomized controlled study.

The aim is to compare the efficacy and safety between single percutaneous nephrolithotomy (sPNL) and antegrade flexible ureteroscopy-assisted percutaneous nephrolithotomy (aPNL) for the treatment of staghorn calculi. A prospective randomized controlled study was conducted at the Second Hospital of Tianjin Medical University. A total of 160 eligible patients were included, with 81 in the sPNL group and 79 in the aPNL group. The study first compared the overall differences between sPNL and aPNL. Then, the patients were divided into two subgroups: Group 1 (with less than 5 stone branches) and Group 2 (with 5 or more stone branches), and the differences between the two subgroups were further analyzed. The results showed that aPNL had a higher stone-free rate (SFR) and required fewer percutaneous tracts, with a shorter operation time compared to sPNL (P < 0.05). Moreover, aPNL significantly reduced the need for staged surgery, particularly in patients with 5 or more stone branches. Moreover, there were no significant differences in the changes of hemoglobin levels and the need for blood transfusions between the sPNL and aPNL groups, and the incidence of multiple tracts was lower in the aPNL group. The two groups showed comparable rates of perioperative complications. We concluded that aPNL resulted in a higher SFR for staghorn calculi, and required fewer multiple percutaneous tracts, reduced the need for staged surgery, and had a shorter operative time than PNL alone, especially for patients with 5 or more stone branches. Furthermore, aPNL did not increase the incidence of surgical complications.

A randomized controlled study of ureteral stent extraction string on patient's quality of life and stent-related complications after percutaneous nephrolithotomy in the prone position.

To demonstrate the Tianjin Institute of Urology (TJIU) technique to place and remove the ureteral stent with extraction string after percutaneous nephrolithotomy (PCNL). Additionally, we aim to compare the pain experienced during stent removal, quality of life during stent retention, and stent-related complications between patients with and without extraction string. 65 patients were included in the final analysis in the string group constructed by the TJIU technique and 66 patients in the conventional double-J ureteral stent (non-string) group. All patients underwent the surgery in a prone position under general anesthesia. They completed the Ureteral Stent Symptom Questionnaire (USSQ) on postoperative days (POD) 7, as well as before their ureteral stent was removed. The visual analogue scale (VAS) pain score (0-10) was completed immediately after the removal of the ureteral stent. Moreover, a specialized person was responsible for recording stent-related complications. All patients completed the USSQ on POD 7, and we did not find a difference in scores in each field. However, there was a significant difference in the "sex" domain before removing the ureteral stent (4.34 vs 3.23; p = 0.01). Notably, the use of extraction string after PCNL could decrease the pain associated with stent removal significantly (mean VAS scores 1.45 vs 2.76; p < 0.01). Extraction string did not increase the incidence of stent-related complications. We concluded that placing a ureteral stent with an extraction string after PCNL reduces the pain of ureteral stent removal without increasing complications such as accidental removal of the stent, febrile urinary tract infection (UTI).

Antitumor synergism between PAK4 silencing and immunogenic phototherapy of engineered extracellular vesicles.

Immunotherapy has revolutionized the landscape of cancer treatment. However, single immunotherapy only works well in a small subset of patients. Combined immunotherapy with antitumor synergism holds considerable potential to boost the therapeutic outcome. Nevertheless, the synergistic, additive or antagonistic antitumor effects of combined immunotherapies have been rarely explored. Herein, we established a novel combined cancer treatment modality by synergizing p21-activated kinase 4 (PAK4) silencing with immunogenic phototherapy in engineered extracellular vesicles (EVs) that were fabricated by coating M1 macrophage-derived EVs on the surface of the nano-complex cores assembled with siRNA against PAK4 and a photoactivatable polyethyleneimine. The engineered EVs induced potent PAK4 silencing and robust immunogenic phototherapy, thus contributing to effective antitumor effects in vitro and in vivo. Moreover, the antitumor synergism of the combined treatment was quantitatively determined by the CompuSyn method. The combination index (CI) and isobologram results confirmed that there was an antitumor synergism for the combined treatment. Furthermore, the dose reduction index (DRI) showed favorable dose reduction, revealing lower toxicity and higher biocompatibility of the engineered EVs. Collectively, the study presents a synergistically potentiated cancer treatment modality by combining PAK4 silencing with immunogenic phototherapy in engineered EVs, which is promising for boosting the therapeutic outcome of cancer immunotherapy.

Photoactivatable Silencing Extracellular Vesicle (PASEV) Sensitizes Cancer Immunotherapy.

Immunotherapy has delivered impressive outcomes in combating tumor malignancies. However, insufficient immune infiltration and poor immunogenicity within the tumor microenvironment (TME) greatly compromise patient response rates. Here, a photoactivatable silencing extracellular vesicle (PASEV) is developed for sensitized cancer immunotherapy. p21-Activated kinase 4 (PAK4) is a newly identified tumor-cell-intrinsic "guard" associated with immune exclusion. Small interfering RNA against PAK4 (siPAK4) is designed and assembled with a photoactivatable reactive-oxygen-species (ROS)-sensitive polymer to form the nanocomplex core, which is further camouflaged by extracellular vesicles from M1 macrophages. The PASEV not only serves as a vehicle for packaging, tumor accumulation, and ROS-responsive release of siPAK4 for potent PAK4 silencing, but also primes the TME through immunogenic phototherapy, thereby simultaneously boosting intratumoral infiltration and immune activation. The combined immunotherapy elicits robust anticancer immunity, thus showing great promise for fighting cancers. This work opens a new avenue to simultaneously boost intratumoral infiltration and immune activation for sensitized cancer immunotherapy.

A dual-functional buformin-mimicking poly(amido amine) for efficient and safe gene delivery.

Biguanides (i.e. metformin, phenformin and buformin) are antidiabetic drugs with potential antitumor effects. Herein, a polycationic polymer, N,N'-bis(cystamine)acrylamide-buformin (CBA-Bu), containing multiple biodegradable disulphide bonds and buformin-mimicking side chains was synthesised. CBA-Bu was equipped with high efficiency and safety profile for gene delivery, meanwhile exhibiting potential antitumor efficacy. As a gene vector, CBA-Bu was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>30 mV) uniform polyplexes that were well resistant to heparin and DNase I. Due to the reduction responsiveness of the disulphide bonds, CBA-Bu/pDNA polyplexes could release the loaded pDNA in the presence of dithiothreitol, and induce extremely low cytotoxicity in NIH/3T3 and U87 MG cells. The transfection results showed that CBA-Bu had a cellular uptake efficiency comparable to 25 kDa PEI, while a significantly higher gene expression level. Additionally, CBA-Bu had a lower IC50 value than its non-biguanide counterpart in two cancer cell lines. Furthermore, CBA-Bu could activate AMPK and inhibit mTOR pathways in U87 MG cells, a mechanism involved in the antitumor effect of biguanides. Taken together, CBA-Bu represented an advanced gene vector combining desirable gene delivery capability with potential antitumor activity, which was promising to achieve enhanced therapeutic efficacy in antitumor gene therapy.

A biodegradable poly(amido amine) based on the antimicrobial polymer polyhexamethylene biguanide for efficient and safe gene delivery.

Inspired by the excellent membrane affinity of antimicrobial polymers, we synthesized a novel biodegradable poly(amino amine) polymer with pendent side chains that mimic the widely used biocide polyhexamethylene biguanide (PHMB) for gene delivery. Michael addition polymerization was utilized to form the polymer scaffold between N,N'-cystaminebisacrylamide (CBA) and N-Boc-1,6-diaminohexane (Boc-DAH) followed by N-Boc deprotection. Then the exposed primary amino groups were partly (about 75%) transformed into biguanide by an addition reaction with dicyandiamide to obtain the final product CBA-DAH-biguanide (CBA-DAH-BG). The polymer CBA-DAH-BG was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>35 mV) polyplexes that were well resistant to heparin and DNase I. Rapid DNA release was observed in the presence of dithiothreitol (DTT), indicating that CBA-DAH-BG was equipped with biodegradability by the cleavage of disulfide bonds, which was helpful for unpacking DNA and decreasing cytotoxicity. CBA-DAH-BG/pDNA polyplexes were characterized by efficient cellular uptake efficacy, extremely low cytotoxicity, and high transfection efficiency in two cell lines (i.e., NIH/3T3 and U87 MG), compared to 25 kDa polyethyleneimine (PEI) and the intermediate product CBA-DAH that were both devoid of biguanide groups. Of note, clathrin-mediated endocytosis and lipid rafts played an important role in the internalization of the polyplexes. Taken together, this strategy described herein may represent an innovative avenue for the design of more advanced nonviral gene vectors with high transfection efficiency and biocompatibility.

Amphoteric poly(amido amine)s with adjustable balance between transfection efficiency and cytotoxicity for gene delivery.

In order to balance transfection efficiency and cytotoxicity as well as screen the optimal polymers for gene delivery, a series of amphoteric copolymers (poly(CBA-AGM/GABA)s) composed of different ratios between agmatine (AGM) and γ-aminobutyric acid (GABA) monomers were synthesized. The AGM containing positively charged guanidinium groups was used to improve transfection efficiency, while the GABA containing negatively charged carboxyl groups was used to decrease cytotoxicity. It is hypothesized that the amphoteric poly(CBA-AGM/GABA)s synthesized at the optimal ratio of both components would well balance transfection efficiency and cytotoxicity. By comparing these polymers' essential features in gene delivery, the ideal ratio between AGM and GABA was optimized. AGM80, which contained 80% AGM and 20% GABA, showed favorable properties for gene delivery, including moderate DNA condensation capacity, high cellular uptake, strong nuclear localization ability, high transfection efficiency, and low cytotoxicity, indicating that this polymer is very promising as a potent and nontoxic gene carrier.

Structure-function relationships of nonviral gene vectors: Lessons from antimicrobial polymers.

In recent years, substantial advances have been achieved in the design and synthesis of nonviral gene vectors. However, lack of effective and biocompatible vectors still remains a major challenge that hinders their application in clinical settings. In the past decade, there has been a rapid expansion of cationic antimicrobial polymers, due to their potent, rapid, and broad-spectrum biocidal activity against resistant microbes, and biocompatible features. Given that antimicrobial polymers share common features with nonviral gene vectors in various aspects, such as membrane affinity, functional groups, physicochemical characteristics, and unique macromolecular architectures, these polymers may provide us with inspirations to overcome challenges in the design of novel vectors toward more safe and efficient gene delivery in clinic. Building off these observations, we provide here an overview of the structure-function relationships of polymers for both antimicrobial applications and gene delivery by elaborating some key structural parameters, including functional groups, charge density, hydrophobic/hydrophilic balance, MW, and macromolecular architectures. By borrowing a leaf from antimicrobial agents, great advancement in the development of newer nonviral gene vectors with high transfection efficiency and biocompatibility will be more promising. STATEMENT OF SIGNIFICANCE: The development of gene delivery is still in the preclinical stage for the lack of effective and biocompatible vectors. Given that antimicrobial polymers share common features with gene vectors in various aspects, such as membrane affinity, functional groups, physicochemical characteristics, and unique macromolecular architectures, these polymers may provide us with inspirations to overcome challenges in the design of novel vectors toward more safe and efficient gene delivery in clinic. In this review, we systematically summarized the structure-function relationships of antimicrobial polymers and gene vectors, with which the design of more advanced nonviral gene vectors is anticipated to be further boosted in the future.

Cell-free synthesis of connexin 43-integrated exosome-mimetic nanoparticles for siRNA delivery.

Exosomes are naturally secreted nanovesicles that have emerged as a promising therapeutic nanodelivery platform, due to their specific composition and biological properties. However, challenges like considerable complexity, low isolation yield, drug payload, and potential safety concerns substantially reduce their pharmaceutical acceptability. Given that the nano-bio-interface is a crucial factor for nanocarrier behavior and function, modification of synthetic nanoparticles with the intrinsic hallmarks of exosomes' membrane to create exosome mimetics could allow for siRNA delivery in a safer and more efficient manner. Herein, connexin 43 (Cx43)-embedded, exosome-mimicking lipid bilayers coated chitosan nanoparticles (Cx43/L/CS NPs) were constructed by using cell-free (CF) synthesis systems with plasmids encoding Cx43 in the presence of lipid-coated CS NPs (L/CS NPs). The integration of de novo synthesized Cx43 into the lipid bilayers of L/CS NPs occurred cotranslationally during one-pot reaction and, more importantly, the integrated Cx43 was functionally active in transport. In addition to considerably lower cytotoxicity (

Exosome-based small RNA delivery: Progress and prospects.

RNA interfering (RNAi), mediated by small interfering RNAs and microRNAs, is currently one of the most promising tools of gene therapy. Small RNAs are capable of inducing specific post-transcriptional gene silencing, providing a potentially effective platform for the treatment of a wide array of diseases. However, similar to other nucleic acid-based drugs, the major hurdle of RNAi therapy is lack of efficient and non-immunogenic delivery vehicles. Currently, viruses, synthetic polymers, and lipid-based carriers are among the most widely studied vehicles for small RNA delivery. However, many drawbacks are reported to be associated with these delivery vehicles. There is a pressing need to replace them with more efficient and better-tolerated approaches. Exosomes secreted from the endocytic compartment of live cells, are a subtype of endogenous extracellular vesicles that transfer genetic and biochemical information among different cells, thus playing an important role in cell-cell communication. Recently, accumulating attention has been focused on harnessing exosomes as nanaocarriers for small RNAs delivery. Due to their natural role in shuttling endogenous nucleic acid in our body, exosomes may exhibit higher delivery efficiency, lower immunogenicity, and better compatibility than existing foreign RNA carriers. Importantly, exosomes own intrinsic homing capacity that can guide small RNAs across natural membranous barriers. Moreover, such a capacity can be further improved by adding appropriate targeting moieties. In this manuscript, we briefly review the progress and challenges of RNAi therapy, and discuss the potential of exosomes' applications in small RNA delivery with focus on the most recent advances in exosome-based small RNA delivery for disease therapy.

Liposome-chaperoned cell-free synthesis for the design of proteoliposomes: Implications for therapeutic delivery.

Cell-free (CF) protein synthesis has emerged as a powerful technique platform for efficient protein production in vitro. Liposomes have been widely studied as therapeutic carriers due to their biocompatibility, biodegradability, low toxicity, flexible surface manipulation, easy preparation, and higher cargo encapsulation capability. However, rapid immune clearance, insufficient targeting capacity, and poor cytoplasmic delivery efficiency substantially restrict their clinical application. The incorporation of functional membrane proteins (MPs) or peptides allows the transfer of biological properties to liposomes and imparts them with improved circulation, increased targeting, and efficient intracellular delivery. Liposome-chaperoned CF synthesis enables production of proteoliposomes in one-step reaction, which not only substantially simplifies the production procedure but also keeps protein functionality intact. Building off these observations, proteoliposomes with integrated MPs represent an excellent candidate for therapeutic delivery. In this review, we describe recent advances in CF synthesis with emphasis on detailing key factors for improving CF expression efficiency. Furthermore, we provide insights into strategies for rational design of proteoliposomal nanodelivery systems via CF synthesis. STATEMENT OF SIGNIFICANCE: Liposome-chaperoned CF synthesis has emerged as a powerful approach for the design of recombinant proteoliposomes in one-step reaction. The incorporation of bioactive MPs or peptides into liposomes via CF synthesis can facilitate the development of proteoliposomal nanodelivery systems with improved circulation, increased targeting, and enhanced cellular delivery capacity. Moreover, by adapting lessons learned from natural delivery vehicles, novel bio-inspired proteoliposomes with enhanced delivery properties could be produced in CF systems. In this review, we first give an overview of CF synthesis with focus on enhancing protein expression in liposome-chaperoned CF systems. Furthermore, we intend to provide insight into harnessing CF-synthesized proteoliposomes for efficient therapeutic delivery.

Functionalized extracellular vesicles as advanced therapeutic nanodelivery systems.

Extracellular vesicles (EVs) are membrane enclosed vesicles that are shed by almost all cell types, and play a fundamental role in cell-to-cell communication. The discovery that EVs are capable of functionally transporting nucleic acid- and protein-based cargoes between cells, rapidly promotes the idea of employing them as drug delivery systems. These endogenous vesicles indeed hold tremendous promise for therapeutic delivery. However, issues associated with exogenously administered EVs, including rapid clearance by the immune system, apparent lack of targeting cell specificity, and insufficient cytoplasmic delivery efficiency, may limit their therapeutic applicability. In this review, we discuss recent research avenues in EV-based therapeutic nanodelivery systems. Furthermore, we narrow our focus on the development of modification strategies to enhance the delivery properties of EVs, and elaborate on how to rationally harness these functionalized vesicles for therapeutic delivery.

Comparison of exosome-mimicking liposomes with conventional liposomes for intracellular delivery of siRNA.

Exosomes have been extensively explored as delivery vehicles due to low immunogenicity, efficient cargo delivery, and possibly intrinsic homing capacity. However, therapeutic application of exosomes is hampered by structural complexity and lack of efficient techniques for isolation and drug loading. Liposomes represent one of the most successful therapeutic nanocarriers, but are frequently criticized by short blood circulation and inefficient intracellular drug delivery. In this circumstance, a promising strategy is to facilitate a positive feedback between two fields. Herein, exosome-mimicking liposomes were formulated with DOPC/SM/Chol/DOPS/DOPE (21/17.5/30/14/17.5, mol/mol), and harnessed for delivery of VEGF siRNA to A549 and HUVEC cells. Compared with Lipo 2000 and DOTAP liposomes, exosome-mimicking liposomes exhibited less than four-fold cytotoxicity but higher storage stability and anti-serum aggregation effect. Exosome-mimicking liposomes appeared to enter A549 cells through membrane fusion, caveolae-mediated endocytosis, and macropinocytosis, while enter HUVEC through caveolae-mediated endocytosis, which revealed that the uptake pathway was dependent on cell types. Notably, exosome-mimicking liposomes exhibited significantly higher cellular uptake and silencing efficiency than PC-Chol liposomes (>three-fold), suggesting the unique lipid composition did enhance the intracellular delivery efficiency of exosome-mimicking liposomes to a significantly greater extent. However, it still remained far from satisfactory delivery as compared to cationic Lipo 2000 and DOTAP liposomes, which warranted further improvement in future research. This study may encourage further pursuit of more exosome-mimicking delivery vehicles with higher efficiency and biocompatibility.

Intracellular distribution and internalization pathways of guanidinylated bioresponsive poly(amido amine)s in gene delivery.

Guanidinylated bioresponsive poly(amido amine)s polymers, CAR-CBA and CHL-CBA, were synthesized by Michael-type addition reaction between guanidine hydrochloride (CAR) or chlorhexidine (CHL) and N,N'-cystaminebisacrylamide (CBA). Previous studies have shown that both polymers had high transfection efficiencies as gene delivery carriers. In this study, we investigated the nucleolus localization abilities and cellular internalization pathways of these two polymers in gene delivery. Each polymer condensed plasmid DNA (pDNA) and formed nanoparticle complexes, and then their transfection studies were performed in MCF-7 cells. Both complexes were found enriched in nucleolus after cellular transfection, and their transfection efficiencies were significantly improved when transfection was performed on MCF-7 cells arrested at M phase. The transfection efficiency of CAR-CBA-pDNA was inhibited by chlorpromazine, and cell endosomes were disrupted after being exposed to CAR-CBA-pDNA. In regards to CHL-CBA-pDNA, its transfection efficiency was not affected by three types of endocytosis inhibitors used in the study, and CHL-CBA-pDNA showed no effect on endosomes. Cellular lactate dehydrogenase release and membrane morphology were changed after cells were transfected by the two complexes. The results indicated that both CAR-CBA and CHL-CBA polymers demonstrated good nucleolus localization abilities. It was beneficial for transfection when cells were arrested at M phase. CAR-CBA-pDNA cellular internalization was involved with clathrin-mediated endocytosis pathway, and escaping from endosomal entrapment, while the cellular uptake of CHL-CBA-pDNA occurs via clathrin- and caveolae-independent mechanism.

Recent advances on extracellular vesicles in therapeutic delivery: Challenges, solutions, and opportunities.

Extracellular vesicles (EVs) are intrinsic mediators of intercellular communication in our body, allowing functional transfer of biomolecules (lipids, proteins, and nucleic acid) between diverse locations. Such an instrumental role evokes a surge of interest within the drug delivery community in tailoring EVs for therapeutic delivery. These vesicles represent a novel generation of drug delivery systems, providing high delivery efficiency, intrinsic targeting properties, and low immunogenicity. In the recent years, considerable research efforts have been directed toward developing safe and efficient EV-based delivery vehicles. Although EVs are shown to harbor great promise in therapeutic delivery, substantial improvements in exploring standardized isolation techniques with high efficiency and robust yield, scalable production, standard procedures for EV storage, efficient loading methods without damaging EV integrity, understanding their in vivo trafficking, and developing novel EV-based nanocarriers are still required before their clinical transformation. In this review, we seek to summarize the recent advance on harnessing EVs for drug delivery with focus on state-of-the-art solutions for overcoming major challenges.

Liquisolid technique and its applications in pharmaceutics.

Most of the newly developed drug candidates are lipophilic and poorly water-soluble. Enhancing the dissolution and bioavailability of these drugs is a major challenge for the pharmaceutical industry. Liquisolid technique, which is based on the conversion of the drug in liquid state into an apparently dry, non-adherent, free flowing and compressible powder, is a novel and advanced approach to tackle the issue. The objective of this article is to present an overview of liquisolid technique and summarize the progress of its applications in pharmaceutics. Low cost, simple processing and great potentials in industrial production are main advantages of this approach. In addition to the enhancement of dissolution rate of poorly water-soluble drugs, this technique is also a fairly new technique to effectively retard drug release. Furthermore, liquisolid technique has been investigated as a tool to minimize the effect of pH variation on drug release and as a promising alternative to conventional coating for the improvement of drug photostability in solid dosage forms. Overall, liquisolid technique is a newly developed and promising tool for enhancing drug dissolution and sustaining drug release, and its potential applications in pharmaceutics are still being broadened.