In this study, poly(lactic acid) (PLA) hollow microspheres with a narrow size distribution and controllable structure were developed by the antisolvent-induced solvent evaporation method. Water-in-oil (W/O) emulsion were produced using the premix membrane emulsification (PME) technique, ensuring a narrow size distribution with controllable particle size. Notably, n-hexane used as an antisolvent promoted the formation of hollow structures by inducing phase separation within the emulsion droplets. Consequently, at an n-hexane to dichloromethane volume ratio of 1:30, the yield of hollow microspheres reached 86.00 +/- 2.69 % per batch. PLA with a molecular weight of 20 kDa provided an optimal balance between emulsion viscosity and structural stability, whereas 10 kDa PLA caused microsphere collapse due to insufficient mechanical strength, and 30 kDa PLA impeded cavity formation due to excessive viscosity. Furthermore, wall thickness ranging from 1.42 +/- 0.11 mu m to 5.91 +/- 0.18 mu m was adjusted by changing PLA concentration (50-125 mg/mL), with cavity integrity confirmed via confocal laser scanning microscopy and cryosection. Overall, the one-step method described here offers a scalable approach for producing uniform hollow polymeric microspheres with controllable wall thickness and high batch-to-batch consistency.

Teriparatide is a representative anabolic agent for the treatment of osteoporosis; however, its therapeutic efficacy relies on intermittent exposure, necessitating frequent administration and thereby limiting long-term patient compliance. To address this limitation, we developed a programmable pulsatile delivery platform based on uniform core-shell microspheres fabricated via a W1/O/W2 double-emulsion process combined with premix membrane emulsification (PME). Through precise regulation of polymer phase separation, teriparatide is preferentially localized within the microsphere core. Core-shell microspheres constructed with PLLA shells of 7, 36, and 78 kDa exhibit well-defined pulsatile release profiles in vitro, each generating a major release event at approximately 7, 14, and 21 days, respectively, with about 40% of the loaded drug discharged during each pulse. In ovariectomized mice, a single administration of the combined microsphere combination formulation enhances bone formation, suppresses bone resorption, and markedly restores trabecular bone microarchitecture over a one-month treatment period, achieving therapeutic outcomes comparable to those of weekly teriparatide solution injections. Collectively, these findings demonstrate that PME-assisted phase separation core-shell microspheres enable synchronized and temporally programmable pulsatile delivery of teriparatide, offering a versatile platform for long-acting peptide therapeutics in osteoporosis management.

Activation of the STING pathway represents a potent strategy for cancer immunotherapy. However, the instability and systemic toxicity of STING agonists, especially cyclic dinucleotides (CDNs), limit their use via local administration with poor efficacy against metastatic or inaccessible tumors. Here, we develop an engineered silicasome nanocarrier for systemic delivery of the CDN ADU-S100 (ADU-Sili). Comprising ADU-S100-loaded mesoporous silica nanoparticles (MSNPs) coated with lipid bilayer, ADU-Sili markedly enhanced tumor accumulation and antitumor efficacy compared with free ADU-S100 and conventional liposomes in vivo. The advantage of systemic delivery was further demonstrated in bilateral tumors: ADU-Sili induced systemic antitumor immunity, suppressing both tumors, whereas free ADU-S100 inhibited only injected tumors. Immune profiling revealed that ADU-Sili promoted dendritic cell maturation in lymph nodes, expanded cytotoxic and memory CD8+ T cells in spleens, elevated intratumoral effector cytokines, and polarized tumor-associated macrophages toward an M1 phenotype. Notably, combining ADU-Sili with immune checkpoint blockade (ICB) synergistically enhanced antitumor efficacy as demonstrated in more clinically relevant orthotopic tumor models. In summary, silicasomes enable effective systemic CDN delivery, eliciting robust immune and antitumor responses and overcoming intratumoral delivery limitations in STING-based cancer immunotherapy.

Function-encoding peptides have emerged as promising biomaterials capable of replicating the robust biological functions of the extracellular matrix (ECM). Nevertheless, the full potential of their sequence designability remains to be explored to develop highly bioactive peptide-based biomaterials with minimal immunogenicity. In this study, chiral peptides are self-assembled into supramolecular hydrogels (FFFKTTKS/fffkttks) incorporating an active sequence derived from collagen hydrolysis, a key ECM factor. While FFFKTTKS (L-type) and fffkttks (D-type) peptide-based hydrogels exhibit comparable viscoelasticity, porosity, and supramolecular architecture, they differ in their nanofiber composition, particularly in helical orientation. In a model of spinal cord injury, the FFFKTTKS hydrogel demonstrates superior neuronal regeneration and motor function recovery compared to its fffkttks counterpart. Further investigations reveal that both FFFKTTKS and fffkttks hydrogels equally promote the expression of ECM-related genes, subsequently regulating nerve cell adhesion, neuronal differentiation, and synaptic regeneration. Notably, the FFFKTTKS hydrogel elicits a mild immune response and exhibits moderate anti-inflammatory properties. In contrast, the fffkttks hydrogel triggers a robust immune response, activating the TNF pathway in microglia in vivo. These findings underscore that nanoscale chiral superstructures of specific peptide sequences can effectively modulate biocapability and neuroregeneration, providing critical insights for the rational design of peptide-based synthetic ECM.

Surface-enhanced Raman scattering (SERS) is an ultrasensitive optical technique that is critical for protein detection and essential for identifying protein structure and concentrations in various biomedical and diagnostic applications. However, achieving highly sensitive and reproducible SERS signals for label-free proteins remains challenging due to their weak Raman signals and structural complexity. In this study, silver nanomushroom arrays (Ag NMAs) as SERS substrates were readily prepared and surface-engineered using a facile template-assisted micro- and nanofabrication approach. The surface of the substrate exhibits nanoscale roughness, long-range order, and hydrophilicity, enabling rapid and uniform dispersion of protein molecules. These molecules are anchored through Ag-S bonds, resulting in ultrasensitive Raman signals driven by strong electromagnetic enhancement effects. The highly ordered array structure improves signal repeatability, achieving a relative standard deviation of as low as 4.32%. Additionally, utilizing the silicon characteristic peak of the SERS substrate as an internal standard significantly reduces measurement errors, allowing for reliable and precise quantitative detection of protein molecules, with a linear correlation coefficient (R2) exceeding 0.96. Ultrasensitive SERS detection and effective protein discrimination via principal component analysis further validate the Ag NMA substrate's potential for universal trace protein detection. This study presents an advanced SERS platform for the sensitive and rapid detection of trace proteins, showcasing significant potential in pharmaceutical research, metabolic studies, diagnostic medicine, and protein engineering.

Hydrogel adhesives exhibit significant potential in various biomedical fields such as wound hemostasis and healing. However, there is a lack of general strategies for preparing hydrogel adhesives that can be adapted to a variety of complex human environments, thus severely impeding their application. Herein, a modular design of hydrogel adhesive systems incorporating genetically engineered polypeptides is developed. In this system, hydrogel networks and protein coacervates are endowed with distinct functions. Each component plays a specific role, while they work synergistically to achieve a balance between adhesive strength and cohesion. Moreover, upon mild triggering, these hydrogel bioadhesives can be easily removed without causing any damage or discomfort to the tissues. To demonstrate its broad applicability, three kinds of hydrogel adhesives are designed and successfully employed in liver, heart, and stomach models. Robust adhesion performance of the hydrogel bioadhesives in vivo for tissue wound hemostasis and healing is showed.

Traditional treatments for periodontitis are limited by their inability to adequately modulate the immune response and control inflammation. Recently, nucleic acid-modified nanomaterials have attracted significant attention for their potential in regulating inflammation. Among these, most nanomaterials, such as spherical nucleic acids, tend to exhibit pro-inflammatory effects. In this study, we identified for the first time that poly-T sequence-modified gold nanorods (PTM AuNRs) possess significant anti-inflammatory properties. The PTM AuNRs demonstrated excellent biocompatibility and efficacy in treating ligation-induced periodontitis. PTM AuNRs modulate immune responses by inhibiting the differentiation of pro-inflammatory M1 macrophages and reducing pro-inflammatory cytokine levels through promoting AMPK activation. When administered via local injection, PTM AuNRs effectively suppress inflammatory response and inflammatory cell infiltration, downregulate inflammatory cytokine levels, and mitigate collagen fiber degradation and alveolar bone loss. Together, these findings highlight PTM AuNRs as a promising and innovative therapeutic strategy for periodontitis management.

A facile and versatile methodology is developed for the synthesis of diverse gold nanostructured arrays employing an oxide secondary template combined with sputtering deposition. A bowl-shaped tin oxide-built array, with fine structure on its bowl edges, is first designed and prepared by solution-dipping of an organic colloidal monolayer, drying, and heating treatment. This array is then used as a secondary template for a gold nanostructured array by sputtering deposition on it. By controlling the solution's concentration and drying rate to adjust the fine structure of the secondary template, various new gold nanostructured arrays with hexagonal arrangement are fabricated, including "graphene-structured" gold nanoarray, non-contact nanoparticle's ring array, closely contacted nanoring array, and bowl/nanoparticle binary composite nanoarray, achieving the structural diversity and morphological tunability of nanoarrays. Additionally, these gold nanostructured arrays can transition from hydrophilic to hydrophobic properties solely by adjusting their surface architecture. Importantly, the bowl-shaped structural units within these gold nanoarrays demonstrate a marked capability for capturing target molecules that can only very weakly interact with plasmonic metals. This work offers an efficient route to achieve the structural diversity of nanoarrays, which is of significance in designing and fabricating foundational materials for the next generation of multifunctional nanodevices. A variety of gold nanostructured arrays are fabricated based on bowl-shaped tin oxide secondary templates with fine structure on their bowl edges, including "graphene-structured" nanoarray, non-contact nanoparticle ring array, closely-contacted nanoring array and bowl/nanoparticle binary composite nanoarray, achieving the structural diversity and morphological modifiability. These nanoarrays have exhibited structure-induced hydrophilic-hydrophobic transition and target molecular trapping effect. image

Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus (T2DM), but its 11-15 h half-life resulted in daily administration, which led to poor patient compliance. This study aimed to solve this problem by developing liraglutide-loaded microspheres with a 1 month sustained release prepared by the W1/O/W2 method combined with the premix membrane emulsification technique to improve therapeutic efficacy. Remarkably, we found that the amphiphilic properties of liraglutide successfully reduced the oil-water interfacial tension, resulting in a stable primary emulsion and decreasing the level of drug leakage into the external water phase. As a result, exceptional drug loading (>8%) and encapsulation efficiency (>85%) of microspheres were achieved. Furthermore, the uniformity in microsphere size facilitated an in-depth exploration of the structural characteristics of liraglutide-loaded microspheres. The results indicated that the dimensions of the internal cavities of the microspheres were significantly influenced by the size of the inner water droplets in the primary emulsion. A denser and more uniform cavity structure decreased the initial burst release, improving the release process of liraglutide from the microspheres. To evaluate the release behavior of liraglutide from microspheres, a set of in vitro release assays and in vivo pharmacodynamics were performed. The liraglutide-loaded microspheres effectively decreased fasting blood glucose (FBG) levels and hemoglobin A1c (HbA1c) levels while enhancing the pancreatic and hepatic functions in db/db mice. In conclusion, liraglutide sustained-release microspheres showed the potential for future clinical applications in the management of T2DM and provided an effective therapeutic approach to overcoming patient compliance issues.

The ability to simultaneously detect multiple volatile organic compounds (VOCs) is crucial for assessing indoor air quality and addressing significant health hazards. In this study, we present a sacrificial template approach for on-chip fabrication of two-dimensional (2D) Ni-doped SnO2 nanoporous sensing films on micro-heater substrates. The technical analysis shows that the resulting honeycomb-like ultrathin Ni-SnO2 sensing layer on a suspended substrate maintains perfect structural integrity and consistency. The Ni-SnO2 sensors exhibit exceptional characteristics, including a ppb-level detection limit, high sensitivity, fast response/recovery time, and signal repeatability for typical VOCs, while operating at a low power consumption of 25 mW. Additionally, the Ni-doping enhances the sensors' cross-sensitivity to various forms of VOCs, while causing a discernible response inhibition towards flammable or exhaust gases. Furthermore, X-ray photoelectron spectroscopy (XPS) and in-situ Raman spectra reveal a Ni2+-substitution induced surface adsorbed oxygen species enrichment mechanism for sensing enhancement. Thus, the developed Ni-SnO2 sensors hold promise as future candidates for reliable air quality assessment by real-time monitoring of overall concentrations of multiple VOCs.

Sustained release microspheres loaded with goserelin are regarded as a promising candidate for treating prostate cancer and other sex hormone diseases. However, their widespread adoption has been hindered by issues such as wide particle size distribution and unstable release characteristics. To address these challenges, we employed a combination of the solid-in-oil-in-water microspheres preparation approach (S/O/W) and innovative premix membrane emulsification technology and deeply investigated the effects of four key parameters on the loaded performance of microspheres and the microscopic mechanisms behind them. With this approach, we successfully produced goserelin-loaded sustained release microspheres of narrow particle size distribution (Span 0.642), remarkable encapsulation efficiency (DL = 4.23 %, EE = 93.98 %), low initial burst release (about 0.50 % within 2 h), and compatibility with small injection needles (23-G, inner diameter 0.33 mm, outer diameter 0.64 mm, maximal force 59 N). In the animal model(administered dose, 2.4 mg·Kg-1), goserelin long-acting sustained release microspheres sustained release for over 32 days, maintaining effective concentrations above 2 ng·mL-1, and effectively reduced serum testosterone concentrations to castration levels (<1.0 ng·mL-1) by day 4, maintaining this inhibition for up to 21 days, exhibiting comparable efficacy to the positive control group. In vivo release kinetics analysis revealed that goserelin-loaded sustained release microspheres exhibited a release pattern dominated by diffusion with corrosion assistance in vivo. In summary, the systematic and comprehensive evaluation of uniform-sized goserelin-loaded sustained release microspheres has highlighted their excellent translational potential, and the study herein may provide new strategies and ideas for the development of microsphere dosage forms.

Chemo/photothermal combination therapy is a promising and practical approach for cancer treatment which calls for certain nanovehicles to achieve the spatiotemporal co-occurrence of photothermal conversion and drug delivery. Herein, we developed a montmorillonite-based Pickering emulsion equipped with a near-infrared photothermal agent (indocyanine green, ICG) and anticarcinogen (paclitaxel, PTX). With both montmorillonite and ICG functioning as interfacial stabilizers, the Pickering emulsion showed good stability and nanoscale droplet size, which were favored for cellular applications. Due to the vast oil-water interface, where the majority of amphiphilic ICG was prone to distribute, the Pickering nanoemulsion could achieve a higher local concentration of ICG than the aqueous solution, therefore leading to a higher local photothermal performance under near-infrared irradiation. The Pickering nanoemulsion exhibited fast cell penetration, which promoted the photothermal therapeutic effect of ICG. Moreover, the inner phase of the Pickering nanoemulsion also facilitated the loading of PTX, further improving its killing efficacy against cancer cells under near-infrared irradiation, because the photothermal conversion of the Pickering nanoemulsion could not only cause heat damage by itself but also promote the loaded PTX to diffuse out and induce cell death. Therefore, this clay-based Pickering nanoemulsion as a nanovehicle could realize the synergy of chemo- and photothermal therapy.

Non-adherence to antiretroviral treatment is a critical obstacle to effectively managing the progression of AIDS and reducing transmission and mortality rates. A promising strategy to address the clinical disadvantages of user-dependent dosing and decrease medication frequency is the development of long-acting antiretrovirals. In this study, we fabricated PLGA microspheres (MS) incorporating the lipopeptide LP-98 (LP-98-MS), which has previously exhibited potent anti-HIV efficacy. Our findings demonstrate that a single-dose injection of LP-98-MS in SHIV-infected rhesus macaques resulted in sustained and gradual release, maintaining antiviral effects at least 28 days. Notably, a single administration of LP-98-MS provided more than 28 days of sustained release, resulting in high-level pre-exposure prophylaxis (PrEP) for rhesus macaques, even providing complete protection when exposed to repeated intravaginal and intrarectal SHIV challenges. Overall, LP-98-MS holds significant potential in reducing medication frequency and shows promising prospects for further development.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used in treating type 2 diabetes (T2D). However, owing to their limited oral bioavailability, most commercially available GLP-1 RAs are administered through frequent subcutaneous injections, which may result in poor patient compliance during clinical treatment. To improve patients' compliance, sustained-release GLP-1 RA-loaded microspheres have been explored. This review is an overview of recent progress and research in GLP-1 RA-loaded microspheres. First, the fabrication methods of GLP-1 RA-loaded microspheres including the coacervation method, emulsion-solvent evaporation method based on agitation, premix membrane emulsification technology, spray drying, microfluidic droplet technology, and supercritical fluid technology are summarized. Next, the strategies for maintaining GLP-1 RAs' stability and activity in microspheres by adding additives and PEGylation are reviewed. Finally, the effect of particle size, drug distribution, the internal structure of microspheres, and the hydrogel/microsphere composite strategy on improved release behavior is summarized.

Ropivacaine (ROP), a new type of amide local anesthetic (LA) with low cardiac and neurotoxicity, is used to treat postoperative pain. However, ROP has a short half-life (t1/2 = 1.8 h) and the analgesic duration of a single-dose injection last only 3-4 h, which cannot meet clinical needs. In order to solve the problem, we combined an O/W emulsion method with a premix membrane emulsion technique to prepare sustained-release ropivacaine-loaded emulsion (ROP-E) with narrow droplets size distribution. As a result, the ROP-E about 8.385 mu m with a span value of 0.737 was obtained. Moreover, the sciatic nerve block model and the cutaneous trunci pinprick model were established to evaluate the efficacy of ROP-E in vivo. The results of the sciatic nerve model showed that the sensory nerve block duration (4.27 h) of ROP-E was significantly prolonged, which was 2.15 and 1.42 folds of ROP injection and Exparel (R) formulation, respectively. Similarly, the motor nerve block duration (3.62 h) was 1.8 and 1.46 folds of ROP injection and Exparel (R) formulation, respectively. Effective analgesia duration of ROP-E was about 18 h, 2.25 folds longer than that of ROP injection in the cutaneous trunci pinprick model. Besides, the ROP-E displayed excellent stability according to the droplet size, drug loading concentration, in vivo and in vitro release. H&E and blood biochemistry showed an insignificant difference between the ROP-E and the ROP injection, which further indicated the safety of ROP-E. These results suggested that ROP-E may be useful for sustained release of local anesthetics to prolong analgesia without causing systemic toxicity.

Gonadotropin-releasing hormone (GnRH) agonists are peptides consisting of nine or ten amino acid residues. GnRH agonists have been applied in the therapy of sexual hormone disorders like prostate cancer, endometriosis, uterine myoma, central precious puberty, and in-vitro fertility. Treatment is achieved by continuous hormone intake and long-term agonists administration, which is usually associated with poor patient compliance. Because GnRH agonists that are administered with the parenteral route are broken down by peptidase, their half-life is short. As a result, developing sustained release for the drug delivery system is significant. Even though some drugs have been successfully delivered with long-acting release microspheres and approved by the Food and Drug Administration (FDA), some challenges remain. This review highlighted current approaches to encapsulate GnRH agonists into delivery systems and strategies encountered during the loading process. Moreover, the following sections provide strategies to improve the release profile, and animal and human studies were summarised.

Low encapsulation efficiency of the drug usually exist in hydrophilic drug which was embedded by hydrophobic materials directly in traditional method. In order to solve this problem, a novel preparation strategy which called “post-loading mode” was innovatively designed in this study: ropivacaine hydrochloride (ROP), a hydrophilic drug used in the field of anesthesia and analgesia, was encapsulated into the pre-prepared porous Poly (lactic-co-glycolic acid) (PLGA) microspheres; the porous PLGA microspheres (PLGA-Ms) with self-healing characteristic were used to obtain ROP-PLGA-Ms (with particle size around were 38 µm), in which drug loading (DL) was 8.72%. A rat sciatic nerve block model was established to evaluate the efficacy of ROP-PLGA-Ms. Exparel®, a bupivacaine liposome suspension approved by the FDA, was defined as reference agents in this study. The results showed that the injection of ROP, Exparel®, and ROP-PLGA-Ms were injected to the peripheral sciatic nerve could lead to motor dysfunction and sensory nerve block unanimously, and the onset time was less than 10 min for all cases. In addition, in comparison with ROP injection and Exparel®, the nerve block time of ROP-PLGA-Ms was significantly prolonged (P < 0.05). Effective analgesia duration of ROP-PLGA-Ms was about 5 h, 2.5 and 1.7 folds longer than that of ROP injection and Exparel®, respectively. The rats in each group could recover eventually within 8 h after administration. H&E showed that no inflammatory reaction was observed at the injection location. Analysis of blood biochemistry showed an insignificant difference between the microsphere experimental group and the negative group, which further indicated the safety of microsphere bioformulation.

为解决抗艾滋药物两亲性脂肽LP-98溶解度低的问题,采用高压均质技术制备LP-98纳米混悬液冻干粉,并对其进行理化性质表征及药代动力学研究.最优制备工艺为:稳定剂为SDS,浓度为0.80wt％,高压均质压力为150MPa,高压均质次数为5次.制备得到的LP-98纳米混悬液冻干粉复溶后平均粒径为261.5±1.1 nm,Zeta电位为-31.5±0.2mV.圆二色光谱仪与单周期病毒感染实验结果显示LP-98的结构与生物活性均未改变.药代动力学结果表明,LP-98纳米混悬液冻干粉生物利用度为原料药的98.1％.LP-98在水中溶解度由184 μg/mL提升至1733 μg/mL,与原料药相比提高了8倍,解决了注射时药物难混悬的问题.

微球制剂是新型的给药系统,其粒径均一性非常重要,不仅影响产品批次间制备重复性,还会影响应用效果.因此,尺寸均一、可控的微球产品是医药制剂的关键核心.本团队成功发展了微孔膜乳化技术,20年来在粒径均一、尺寸可控微球的制备和应用方面进行了系统性研究.均一的微球制剂的优势有:绿色环保、降低成本,利于规模放大,批次间重复性好,利于研究构效关系.本团队制备的均一载药微球已成功应用于缓释制剂、疫苗递送及恶性肿瘤治疗中.