Synergistically engineered in-situ self-assembled heterostructure composite nanofiber cathode with superior oxygen reduction reaction catalysis for solid oxide fuel cells.

The engineering and exploration of cathode materials to achieve superior oxygen reduction catalytic activity and resistance to CO2 are crucial for enhancing the performance of solid oxide fuel cells (SOFCs). Herein, a novel heterostructure composite nanofiber cathode comprised of PrBa0.5Sr0.5Co2O5+δ and Ce0.8Pr0.2O1.9 (PBSC-CPO-ES) was prepared for the first time through a synergistic approach involving in-situ self-assembly and electrostatic spinning techniques. PBSC-CPO-ES exhibits exceptionally high oxygen reduction catalytic activity and CO2 resistance, which is attributed to its unique nanofiber microstructure and abundant presence of heterointerfaces, significantly accelerating the charge transfer process, surface exchange and bulk diffusion of oxygen. The introduction of CPO not only effectively reduces the thermal expansion of PBSC but also changes the characteristics of oxygen ion transport anisotropy in layered perovskite materials, forming three-dimensional oxygen ion transport pathways. At 750 °C, the single cell employing the PBSC-CPO-ES heterostructure nanofiber attains an impressive peak power density of 1363 mW cm-2. This represents a notable 60.7 % improvement in comparison to the single-phase PBSC powder. Moreover, PBSC-CPO-ES exhibits excellent CO2 tolerance and performance recovery after CO2 exposure. This work provides new perspectives to the design and advancement of future high-performance and high-stability SOFC cathode materials.

Metal-organic polymer enables efficient organic photoelectrochemical transistor biosensing.

The field of organic photoelectrochemical transistor (OPECT) is newly emerged, with increasing efforts attempting to utilize its properties in biological sensing. Advanced materials with new physicochemical properties have proven important to this end. Herein, we report a metal-organic polymers-gated OPECT biosensing exemplified by CuⅠ-arylacetylide polymers (CuAs)-modulated poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) channel. Both the photoelectrochemical properties and gating capability of CuAs are explored and optimized for high-efficacy photogating. Morever, based on its inherent structure, the specific reaction between CuAs and sulfur ions (S2-) is revealed and S2--mediated microRNA-21 detection is realized by linking with nucleic acid amplification and alkaline phosphatase catalytic chemistry. This work introduces metal-organic polymers as gating materials for OPECT biosensing.

Ni-Based Catalysts for CO2 Methanation: Exploring the Support Role in Structure-Activity Relationships.

The catalytic hydrogenation of CO2 to methane is one of the highly researched areas for the production of chemical fuels. The activity of catalyst is largely affected by support type and metal-support interaction deriving from the special method during catalyst preparation. Hence, we employed a simple solvothermal technique to synthesize Ni-based catalysts with different supports and studied the support role (CeO2, Al2O3, ZrO2, and La2O3) on structure-activity relationships in CO2 methanation. It is found that catalyst morphology can be altered by only changing the support precursors during synthesis, and therefore their catalytic behaviours were significantly affected. The Ni/Al2O3 with a core-shell morphology prepared herein exhibited a higher activity than the catalyst prepared with a common wet impregnation method. To have a comprehensive understanding for structure-activity relationships, advanced characterization (e. g., synchrotron radiation-based XAS and photoionization mass spectrometry) and in-situ diffuse reflectance infrared Fourier transform spectroscopy experiments were conducted. This research opens an avenue to further delve into the role of support on morphologies that can greatly enhance catalytic activity during CO2 methanation.

Development of a drying method for proteins based on protein-hyaluronic acid precipitation.

This study aims to develop a new method to dry proteins based on protein-hyaluronic acid (HA) precipitation and apply the precipitation-redissolution technique to develop highly concentrated protein formulations. Lysozyme was used as a model protein and HA with various molecular weights (MW) were investigated. Under low ionic strength, low-MW HA (e.g., MW: around 5 K) did not induce lysozyme precipitation. Conversely, high-MW HA (e.g., MW: approximately from 40 K to 1.5 M) precipitated more than 90 % of lysozyme. The dried lysozyme-HA precipitates had moisture levels between 4 % and 5 %. The lysozyme-HA precipitates could be redissolved using PBS (pH 7.4, ionic strength: ∼ 163 mM). The viscosity of the reconstituted solution was dependent on HA MW, e.g., 4 cP for HA40K, and 155 cP for HA1.5 M, suggesting low-MW HA might be a proper excipient for highly concentrated solution formulations for subcutaneous/intraocular injection and high-MW HA may fit for other applications. The tertiary structure of lysozyme after the precipitation-redissolution steps had no significant difference from that of the original lysozyme as confirmed by fluorescence spectroscopy. The denaturation temperature of lysozyme after the precipitation-redissolution steps and that of the original lysozyme were close, indicating they possessed similar thermal stability. The accelerated stability study revealed that lysozyme stored in the dry precipitates was more physically stable than that in the buffer solution. Overall, this new drying technique is suitable for drying proteins and exhibits several benefits such as minimum energy consumption, cost effectiveness, high production yield, and mild processing conditions. In addition, the precipitation-redissolution technique proposed in this study can potentially be used to develop highly concentrated formulations, especially for proteins experiencing poor stability in the liquid state.

Construction of an Anoikis-Related Gene Prognostic Signature and Identification of ANGPTL4 as a Key Oncogene in Lung Adenocarcinoma.

Anoikis plays an important role in cancer invasion and metastasis. However, the role of anoikis-related genes, AnRGs, in lung adenocarcinoma (LUAD) is not clear. First, anoikis-related genes (AnRGs) were obtained from the Genecard database. Second, the prognostic risk model of AnRGs was established by univariate Cox analysis, the Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox analysis. Finally, in vitro cell experiments were carried out to determine the expression and function of the key gene AnRGs. Three AnRGs (angiopoietin-like 4, ANGPTL4; Cyclin-Dependent Kinase Inhibitor 3, CDKN3; Solute Carrier Organic Anion Transporter Family Member 1B3, SLCO1B3) were screened for the construction of risk prediction model. Additionally, ANGPTL4 was significantly highly expressed in tumor cells, and the knockdown of ANGPTL4 expression on tumor cells could inhibit tumor cell migration and apoptosis. Constructing a risk model based on anoikis-related genes can effectively differentiate the prognosis of LUAD. ANGPTL4 can be used as a potential new target for LUAD treatment.

CDC6 may serve as an indicator of lung adenocarcinoma prognosis and progression based on TCGA and GEO data mining and experimental analyses.

Lung adenocarcinoma (LUAD) is one of the most lethal types of cancer worldwide, and accurately predicting patient prognosis is an important challenge. Gene prediction models, which are known for their simplicity and efficiency, have the potential to be used for prognostic predictions. However, the availability of models with true clinical value is limited. The present study integrated tissue sequencing and the clinical information of patients with LUAD from The Cancer Genome Atlas and Gene Expression Omnibus databases using bioinformatics. This comprehensive approach enabled the identification of 252 differentially expressed genes. Subsequently, univariate and multivariate Cox analyses were performed using these genes, and 14 and 3 genes [including cell division cycle 6 (CDC6), hyaluronan mediated motility receptor and STIL centriolar assembly protein] were selected for the construction of two prognostic models. Notably, the 3­gene prognostic model exhibited a comparable predictive ability to that of the 14­gene model. Functionally, pathway enrichment analysis revealed that CDC6 played a role in regulating the cell cycle and promoting tumor staging. To further investigate the relevance of CDC6, in vitro experiments involving the downregulation of CDC6 expression were conducted, which resulted in significant inhibition of tumor cell migration, invasion and proliferation. Moreover, in vivo experiments demonstrated that downregulating CDC6 expression significantly reduced the burden and metastasis of in situ lung tumors in mice. These findings suggested that CDC6 may be a critical gene involved in the development and prognosis of LUAD. In summary, the present study successfully constructed a simple yet accurate prognostic prediction model consisting of 3 genes. Additionally, the functional importance of CDC6 as a key gene in the model was identified. These findings lay a crucial foundation for further exploration of prognostic prediction models and a deeper understanding of the functional mechanisms of CDC6. Notably, these results have potential clinical implications for improving personalized treatment and prognosis evaluation for patients with LUAD.

Dealuminated Beta zeolite reverses Ostwald ripening for durable copper nanoparticle catalysts.

Copper nanoparticle-based catalysts have been extensively applied in industry, but the nanoparticles tend to sinter into larger ones in the chemical atmospheres, which is detrimental to catalyst performance. In this work, we used dealuminated Beta zeolite to support copper nanoparticles (Cu/Beta-deAl) and showed that these particles become smaller in methanol vapor at 200°C, decreasing from ~5.6 to ~2.4 nanometers in diameter, which is opposite to the general sintering phenomenon. A reverse ripening process was discovered, whereby migratable copper sites activated by methanol were trapped by silanol nests and the copper species in the nests acted as new nucleation sites for the formation of small nanoparticles. This feature reversed the general sintering channel, resulting in robust catalysts for dimethyl oxalate hydrogenation performed with supported copper nanoparticles for use in industry.

Molecular Dynamics Simulation of an Iron(III) Binding Site on the Fc Domain of IgG1 Relevant for Visible Light-Induced Protein Fragmentation.

Molecular dynamics simulations were employed to investigate the interaction between Fe(III) and an iron-binding site composed of THR259, ASP252, and GLU261 on the Fc domain of an IgG1. The goal was to provide microscopic mechanistic information for the photochemical, iron-dependent site-specific oxidative fragmentation of IgG1 at THR259 reported in our previous paper. The distance between Fe(III) and residues of interest as well as the binding pocket size was examined for both protonated and deprotonated THR259. The Fe(III) binding free energy (ΔG) was estimated by using an umbrella sampling approach. The pKa shift of the THR259 hydroxyl group caused by the presence of nearby Fe(III) was estimated based on a thermodynamic cycle. The simulation results show that Fe(III) resides inside the proposed binding pocket and profoundly changes the pocket configuration. The ΔG values indicate that the pocket possesses a strong binding affinity for Fe(III). Furthermore, Fe(III) profoundly lowers the pKa value of the THR259 hydroxyl group by 5.4 pKa units.

Variability in the temporal dynamics of object-based attentional selection.

Our attention can be directed to specific locations in our visual field (space-based attention), or to specific objects (object-based attention). However, object-based attention tends to be less pronounced than space-based attention and can vary greatly between individuals. Here we investigated whether the low prevalence of object-based effects is related to variability in the temporal dynamics of attentional selection. We manipulated cue-to-target intervals from 50 to 600 ms in a two-rectangle discrimination task. Space- and object-based effects were measured at the group level and for individual participants. We used bootstrapping to highlight cue-to-target intervals with maximal space- and object-based effects, and fast Fourier transform (FFT) to investigate rhythmic sampling of locations within and between objects. Whereas overall, space-based effects were robust and stable across all cue-to-target intervals for most participants, object-based effects were small and were only found for a small subset of participants in the different cue-to-target intervals. In the frequency domain, only a small number of participants exhibited significant periodicities, prompting the need for further investigation and consideration. Overall, our study suggests variability in the temporal dynamics of object-based effects underlying their low prevalence, a finding that needs to be further investigated in future studies.

Emerging Process Modeling Capabilities for Dry Powder Operations for Inhaled Formulations.

Dry powder inhaler (DPI) products are commonly formulated as a mixture of micronized drug particles and large carrier particles, with or without additional fine particle excipients, followed by final powder filling into dose containment systems such as capsules, blisters, or reservoirs. DPI product manufacturing consists of a series of unit operations, including particle size reduction, blending, and filling. This review provides an overview of the relevant critical process parameters used for jet milling, high-shear blending, and dosator/drum capsule filling operations across commonly utilized instruments. Further, this review describes the recent achievements regarding the application of empirical and mechanistic models, especially discrete element method (DEM) simulation, in DPI process development. Although to date only limited modeling/simulation work has been accomplished, in the authors' perspective, process design and development are destined to be more modeling/simulation driven with the emphasis on evaluating the impact of material attributes/process parameters on process performance. The advancement of computational power is expected to enable modeling/simulation approaches to tackle more complex problems with better accuracy when dealing with real-world DPI process operations.

Temporal trends in physical fitness among Chinese children and adolescents from 2000 to 2019 and analysis of social-ecological factors.

This study aimed to estimate temporal trends in physical fitness (PF) by regions, age groups and nutritional status among Chinese children and adolescents and to longitudinally examine PF determinants based on social-ecological model. Participants (n = 68,265) aged 7-18 were from five successive national surveys (2000 to 2019). Six tested items of PF were calculated as PF indicator (PFI), which was used to divide participants into two categories: low vs. moderate/high. One-way analysis of variance was used to compare difference and change trend of PFI. Linear regression evaluated relationship between PFI and body mass index (BMI), and logistic regression assessed association between PFI and factors of behaviours and lifestyles on individual-, family- and school-level based on the social-ecological model. PFI declined sharply from 2000 to 2010, increased slightly from 2010 to 2014 and then edged down in 2019. Students with moderate BMI and students in urban areas tended to have higher PFI, and larger increase of PFI was found in students aged 7-9 and 13-15 after 2010. Several determinants on individual-, family- and school-level related to PFI. Efforts to develop PF mainly include increasing PA and reducing sedentary behaviours by facilitating home-school collaboration and emphasizing age-, region- and BMI-specific actions.

The association between various dimensions of sleep parameters and mental health: A large cross-sectional study of 13554 Chinese students.

OBJECTIVES: We aimed to investigate the association between multiple sleep variables and mental health among Chinese students aged 9-22. METHOD: We stratified the included 13,554 students by educational levels. Sleep parameters contained sleep duration on school days and weekends, napping time, chronotype and social jetlag (SJL), which were calculated via questionnaires. Individual psychological well-being and distress were assessed by Warwick-Edinburgh mental Well-being scale and the Kessler Psychological Distress Scale 10 respectively. The multiple linear and binary logistic regression were applied to analyze the association of sleep with mental health. RESULTS: Short sleep on school days showed significantly positive association with psychological problems. While among senior high school students, we found reverse result that sleeping less might negatively associated with more severe distress (7-8 h: aOR = 0.67, 95% CI: 0.46, 0.97). The association of sleep duration with mental health was attenuated a lot on weekends. The chronotype was significantly related with mental health in primary and junior high school: intermediate chronotype (vs late chronotype) was associated with greater wellbeing (ß = 1.03, 95% CI: 0.09, 1.96; ß = 1.89, 95% CI: 0.81, 2.97) and less distress (aOR = 0.78, 95% CI: 0.60, 1.00; aOR = 0.73, 95% CI: 0.58, 0.91). The relationship between SJL, napping duration and psychological health problems were also observed in some educational levels. CONCLUSION: Sleep deprivation on school days, late chronotype and SJL were positively associated with worse mental health in our study, which differed among various educational stages.

Associations of multiple sleep dimensions with overall and abdominal obesity among children and adolescents: a population-based cross-sectional study.

BACKGROUND: The relationship of insufficient sleep with the increased risk of obesity has been reported, but less is known about other sleep dimensions in the sleep-obesity associations. OBJECTIVES: To assess the associations of multiple sleep dimensions with overall and abdominal obesity among Chinese students. METHODS: This was a cross-sectional study involving 10,686 Han students aged 9-18 from Chinese National Survey on Students' Constitution and Health (CNSSCH). We collected sex, age, regions, parental educational levels, physical activity duration and sleep-related information by questionnaire survey, and also conducted anthropometric measurements including height, weight and waist circumference (WC). Unadjusted and adjusted binary logistic regression models were used to estimate the associations of sleep-related dimensions with obesity-related indicators. RESULTS: Short sleep duration was associated with higher body mass index (BMI), larger WC and higher waist-to-height ratio (WHtR) in 9-12 and 16-18 age groups, whereas prolonged sleep duration on weekday was associated with higher BMI in 13-15 age group. Non-habitual midday napping and midday napping ≤0.5 h/d (vs 0.5 to 1 h/d) increased the risk of higher BMI in 13-15 age group, and the former was also associated with larger WC in 9-12 age group. Late bedtime was associated with larger WC and higher WHtR in 9-12 age group and with higher BMI and WHtR in 13-15 age group. Students aged 9-12 with social jet lag ≥2 h were found to have greater BMI after adjustment (Odds Ratio: 1.421; 95% confidence interval: 1.066-1.894). CONCLUSIONS: Short or overlong sleep duration, late bedtime and great social jet lag were associated with higher prevalence of overall or abdominal obesity, while moderate midday napping can effectively decrease the risk. Those findings may assist in developing preventive strategies to combat obesity epidemic.

Development of Drug Release Model for Suspensions in ESCAR (Emulator of SubCutaneous Absorption and Release).

We recently developed an in vitro testing system, namely, ESCAR (Emulator of SubCutaneous Absorption and Release). The objective of this work was to investigate drug release behaviors of unmilled and milled suspensions in ESCAR. A mass transport-based model was developed to describe the multi-step drug release process, including drug dissolution, particle settling, drug distribution/partition, and drug permeation through the membrane(s). To address the particle settling effect, a correction factor was included in the model and its value was obtained by data fitting. It was found that, for both suspensions, (i) the experimental data of various dose/formulation combinations could be fit by the developed model; (ii) the dose effect on drug release was offset by the particle settling effect. This model may help to reduce experimental efforts and facilitate subcutaneous suspension formulation development using ESCAR.

Biorelevant Dissolution Method Considerations for the Appropriate Evaluation of Amorphous Solid Dispersions: are Two Stages Necessary?

Biorelevant dissolution testing has been widely used to better understand a drug or formulation's behavior in the human gastrointestinal (GI) tract. The successful evaluation of biorelevant dissolution behavior requires recognizing the importance of utilizing suitable biorelevant media in conjunction with an appropriate dissolution method, especially for supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs). However, most conventional biorelevant dissolution testing methods are not able to accurately reflect the dissolution, supersaturation, and precipitation tendencies of a drug or formulation, which could misinform ASD formulation screening and optimization. In this study, we developed a single compartment 2-stage pH-shift dissolution testing method to simulate the changes in pH, media composition, and transit time in the GI tract, and results were compared against the conventional single compartment 1-stage dissolution method. Nine model drugs were selected based on their ionization properties (i.e. acid, base or neutral) and precipitation tendency (i.e. moderate or slow crystallizer). The dissolution results confirmed that 2-stage pH-shift dissolution is the preferred biorelevant dissolution method to assess non-ionized weak base (nifedipine) and neutral (griseofulvin) compounds exhibiting a moderate precipitation rate from solution when formulated as ASDs. Finally, we designed a flowchart guidance for the appropriate biorelevant dissolution performance characterization of different categories of ASD formulations.

Jasmonate-based warfare between the pathogenic intruder and host plant: who wins?

Plants and microbial pathogens often engage in a fierce war that determines their survival. Host plants have evolved sophisticated regulatory mechanisms to fine-tune defense responses to counter attacks from pathogens, while pathogens often hijack the lipid-derived phytohormone jasmonate to cause hormonal signaling imbalances for efficient infection. This review focuses on the jasmonate-based warfare between host plants and pathogenic intruders, and further discusses approaches to uncouple plant growth and defense tradeoffs in crop breeding.

Trends of overweight and obesity prevalence in school-aged children among Henan Province from 2000 to 2019.

Objectives: Overweight and obesity are harmful to human health. However, the latest trends of Chinese childhood overweight and obesity prevalence are not available. The aim of this study was to examine the trends from 2000 to 2019 among students in China. Methods: We analyzed data of 66,072 students in the Chinese National Survey on Students' Constitution and Health from 2000 to 2019. Overweight and obesity were defined based on the standard formulated by the International Obesity Task Force (IOTF standard), the World Health Organization (WHO standard), and the Working Group on Obesity in China (WGOC standard), respectively. The χ2-test was used to test the trends of overweight and obesity prevalence and logistic regression was conducted to evaluate the prevalence odds ratios of boys vs. girls and urban vs. rural areas. Results: The prevalence of obesity/overweight and obesity combined was 6.03/23.58% (IOTF standard), 10.56/25.88% (WGOC standard) and 10.75/29.69% (WHO standard) in 2019. From 2000 to 2019, according to the WGOC standard, the prevalence increased from 2.51 to 10.56% for obesity and increased from 9.81 to 25.88% for overweight and obesity combined (P for trend < 0.001). Obesity/overweight and obesity were greater problems in boys than girls and urban than rural areas, but urban-rural differences decreased over time. Conclusion: Overweight and obesity prevalence increased significantly in children and adolescents in China from 2000 to 2019. The prevalence of overweight and obesity in rural areas may contribute to a large percentage of children with overweight and obesity.

Multidimensional self-rating biological rhythm disorder and its association with depression and anxiety symptoms among adolescents aged 11-23 years: a school-based cross-sectional study from China.

BACKGROUND: Depression and anxiety are topical concerns worldwide, especially among adolescents. Besides, biological rhythm disorder as a candidate mechanism for mood disorders is highly prevalent, but relevant research among adolescents in China is presently limited. We conducted the present study to investigate the distribution of multi-dimensional self-rating biological rhythm disorder and the association of self-rating biological rhythm disorders with depression and anxiety symptoms among Chinese adolescents in different academic stages. METHODS: In the cross-sectional study, 3693 students aged 11-23 from Zhengzhou City, Henan Province, China were included. The Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder (GAD-7) were used to evaluate symptoms of depression and anxiety, respectively. Additionally, the Self-Rating of Biological Rhythm Disorder for Adolescents (SBRDA) was used to assess status of biological rhythm disorders. Multivariate logistic regression was developed to explore factors potentially associated with symptoms of depression and anxiety stratified by academic stages. RESULTS: Among all participants, 44.14 and 36.15% suffered from depression and anxiety symptoms, respectively. On average, participants scored 74.66 ± 19.37 on the measure of total biological rhythm disorder. Adjusted for demographic confounding factors, the logistic regression analysis showed higher scores of total biological rhythm disorder were associated with more severe depression (OR = 14.38, 95%CI: 11.38-18.16) and anxiety symptoms (OR = 11.63, 95%CI: 9.14-14.81). The similar results were also found in the stratified analysis by academic stages. CONCLUSIONS: Self-rating biological rhythm disorders are significantly associated with depression and anxiety symptoms among adolescents. Discrepancy across academic stages should also be taken into account in establishing public health strategies.

Development of an In Vitro System To Emulate an In Vivo Subcutaneous Environment: Small Molecule Drug Assessment.

A reliable in vitro system can support and guide the development of subcutaneous (SC) drug products. Although several in vitro systems have been developed, they have some limitations, which may hinder them from getting more engaged in SC drug product development. This study sought to develop a novel in vitro system, namely, Emulator of SubCutaneous Absorption and Release (ESCAR), to better emulate the in vivo SC environment and predict the fate of drugs in SC delivery. ESCAR was designed using computer-aided design (CAD) software and fabricated using the three-dimensional (3D) printing technique. ESCAR has a design of two acceptor chambers representing the blood uptake pathway and the lymphatic uptake pathway, respectively, although only the blood uptake pathway was investigated for small molecules in this study. Via conducting a DoE factor screening study using acetaminophen solution, the relationship of the output (drug release from the "SC" chamber to the "blood circulation" chamber) and the input parameters could be modeled using a variety of methods, including polynomial equations, machine learning methods, and Monte Carlo simulation-based methods. The results suggested that the hyaluronic acid (HA) concentration was a critical parameter, whereas the influence of the injection volume and injection position was not substantial. An in vitro-in vivo correlation (IVIVC) study was developed using griseofulvin suspension to explore the feasibility of applying ESCAR in formulation development and bioequivalence studies. The developed LEVEL A IVIVC model demonstrated that the in vivo PK profile could be correlated with the in vitro release profile. Therefore, using this model, for new formulations, only in vitro studies need to be conducted in ESCAR, and in vivo studies might be waived. In conclusion, ESCAR had important implications for research and development and quality control of SC drug products. Future work would be focused on further optimizing ESCAR and expanding its applications via assessing more types of molecules and formulations.

Advanced Formulations/Drug Delivery Systems for Subcutaneous Delivery of Protein-Based Biotherapeutics.

Multiple advanced formulations and drug delivery systems (DDSs) have been developed to deliver protein-based biotherapeutics via the subcutaneous (SC) route. These formulations/DDSs include high-concentration solution, co-formulation of two or more proteins, large volume injection, protein cluster/complex, suspension, nanoparticle, microparticle, and hydrogel. These advanced systems provide clinical benefits related to efficacy and safety, but meanwhile, have more complicated formulations and manufacturing processes compared to conventional solution formulations. To develop a fit-for-purpose formulation/DDS for SC delivery, scientists need to consider multiple factors, such as the primary indication, targeted site, immunogenicity, compatibility, biopharmaceutics, patient compliance, etc. Next, they need to develop appropriate formulation (s) and manufacturing processes using the QbD principle and have a control strategy. This paper aims to provide a comprehensive review of advanced formulations/DDSs recently developed for SC delivery of proteins, as well as some knowledge gaps and potential strategies to narrow them through future research.