Phytochromes enhance SOS2-mediated PIF1 and PIF3 phosphorylation and degradation to promote Arabidopsis salt tolerance.

Soil salinity is one of the most detrimental abiotic stresses affecting plant survival, and light is a core environmental signal regulating plant growth and responses to abiotic stress. However, how light modulates the plant's response to salt stress remains largely obscure. Here, we show that Arabidopsis (Arabidopsis thaliana) seedlings are more tolerant to salt stress in the light than in the dark, and that the photoreceptors phytochrome A (phyA) and phyB are involved in this tolerance mechanism. We further show that phyA and phyB physically interact with the salt tolerance regulator SALT OVERLY SENSITIVE2 (SOS2) in the cytosol and nucleus, and enhance salt-activated SOS2 kinase activity in the light. Moreover, SOS2 directly interacts with and phosphorylates PHYTOCHROME-INTERACTING FACTORS PIF1 and PIF3 in the nucleus. Accordingly, PIFs act as negative regulators of plant salt tolerance, and SOS2 phosphorylation of PIF1 and PIF3 decreases their stability and relieves their repressive effect on plant salt tolerance in both light and dark conditions. Together, our study demonstrates that photoactivated phyA and phyB promote plant salt tolerance by increasing SOS2-mediated phosphorylation and degradation of PIF1 and PIF3, thus broadening our understanding of how plants adapt to salt stress according to their dynamic light environment.

SALT OVERLY SENSITIVE2 stabilizes phytochrome-interacting factors PIF4 and PIF5 to promote Arabidopsis shade avoidance.

Sun-loving plants trigger the shade avoidance syndrome (SAS) to compete against their neighbors for sunlight. Phytochromes are plant red (R) and far-red (FR) light photoreceptors that play a major role in perceiving the shading signals and triggering SAS. Shade induces a reduction in the level of active phytochrome B (phyB), thus increasing the abundance of PHYTOCHROME-INTERACTING FACTORS (PIFs), a group of growth-promoting transcription factors. However, whether other factors are involved in modulating PIF activity in the shade remains largely obscure. Here, we show that SALT OVERLY SENSITIVE2 (SOS2), a protein kinase essential for salt tolerance, positively regulates SAS in Arabidopsis thaliana. SOS2 directly phosphorylates PIF4 and PIF5 at a serine residue close to their conserved motif for binding to active phyB. This phosphorylation thus decreases their interaction with phyB and posttranslationally promotes PIF4 and PIF5 protein accumulation. Notably, the role of SOS2 in regulating PIF4 and PIF5 protein abundance and SAS is more prominent under salt stress. Moreover, phyA and phyB physically interact with SOS2 and promote SOS2 kinase activity in the light. Collectively, our study uncovers an unexpected role of salt-activated SOS2 in promoting SAS by modulating the phyB-PIF module, providing insight into the coordinated response of plants to salt stress and shade.

Reconstitution of phytochrome A-mediated light modulation of the ABA signaling pathways in yeast.

Abscisic acid (ABA), a classical plant hormone, plays an essential role in plant adaptation to environmental stresses. The ABA signaling mechanisms have been extensively investigated, and it was shown that the PYR1 (PYRABACTIN RESISTANCE1)/PYL (PYR1-LIKE)/RCAR (REGULATORY COMPONENT OF ABA RECEPTOR) ABA receptors, the PP2C coreceptors, and the SnRK2 protein kinases constitute the core ABA signaling module responsible for ABA perception and initiation of downstream responses. We recently showed that ABA signaling is modulated by light signals, but the underlying molecular mechanisms remain largely obscure. In this study, we established a system in yeast cells that was not only successful in reconstituting a complete ABA signaling pathway, from hormone perception to ABA-responsive gene expression, but also suitable for functionally characterizing the regulatory roles of additional factors of ABA signaling. Using this system, we analyzed the roles of several light signaling components, including the red and far-red light photoreceptors phytochrome A (phyA) and phyB, and the photomorphogenic central repressor COP1, in the regulation of ABA signaling. Our results showed that both phyA and phyB negatively regulated ABA signaling, whereas COP1 positively regulated ABA signaling in yeast cells. Further analyses showed that photoactivated phyA interacted with the ABA coreceptors ABI1 and ABI2 to decrease their interactions with the ABA receptor PYR1. Together, data from our reconstituted yeast ABA signaling system provide evidence that photoactivated photoreceptors attenuate ABA signaling by directly interacting with the key components of the core ABA signaling module, thus conferring enhanced ABA tolerance to light-grown plants.

Molecular mechanisms underlying coordinated responses of plants to shade and environmental stresses.

Shade avoidance syndrome (SAS) is triggered by a low ratio of red (R) to far-red (FR) light (R/FR ratio), which is caused by neighbor detection and/or canopy shade. In order to compete for the limited light, plants elongate hypocotyls and petioles by deactivating phytochrome B (phyB), a major R light photoreceptor, thus releasing its inhibition of the growth-promoting transcription factors PHYTOCHROME-INTERACTING FACTORs. Under natural conditions, plants must cope with abiotic stresses such as drought, soil salinity, and extreme temperatures, and biotic stresses such as pathogens and pests. Plants have evolved sophisticated mechanisms to simultaneously deal with multiple environmental stresses. In this review, we will summarize recent major advances in our understanding of how plants coordinately respond to shade and environmental stresses, and will also discuss the important questions for future research. A deep understanding of how plants synergistically respond to shade together with abiotic and biotic stresses will facilitate the design and breeding of new crop varieties with enhanced tolerance to high-density planting and environmental stresses.

Mutual upregulation of HY5 and TZP in mediating phytochrome A signaling.

Phytochrome A (phyA) is the far-red (FR) light photoreceptor in plants that is essential for seedling de-etiolation under FR-rich environments, such as canopy shade. TANDEM ZINC-FINGER/PLUS3 (TZP) was recently identified as a key component of phyA signal transduction in Arabidopsis thaliana; however, how TZP is integrated into the phyA signaling networks remains largely obscure. Here, we demonstrate that ELONGATED HYPOCOTYL5 (HY5), a well-characterized transcription factor promoting photomorphogenesis, mediates FR light induction of TZP expression by directly binding to a G-box motif in the TZP promoter. Furthermore, TZP physically interacts with CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), an E3 ubiquitin ligase targeting HY5 for 26S proteasome-mediated degradation, and this interaction inhibits COP1 interaction with HY5. Consistent with those results, TZP post-translationally promotes HY5 protein stability in FR light, and in turn, TZP protein itself is destabilized by COP1 in both dark and FR light conditions. Moreover, tzp hy5 double mutants display an additive phenotype relative to their respective single mutants under high FR light intensities, indicating that TZP and HY5 also function in largely independent pathways. Together, our data demonstrate that HY5 and TZP mutually upregulate each other in transmitting the FR light signal, thus providing insights into the complicated but delicate control of phyA signaling networks.

The cold response regulator CBF1 promotes Arabidopsis hypocotyl growth at ambient temperatures.

Light and temperature are two core environmental factors that coordinately regulate plant growth and survival throughout their entire life cycle. However, the mechanisms integrating light and temperature signaling pathways in plants remain poorly understood. Here, we report that CBF1, an AP2/ERF-family transcription factor essential for plant cold acclimation, promotes hypocotyl growth under ambient temperatures in Arabidopsis. We show that CBF1 increases the protein abundance of PIF4 and PIF5, two phytochrome-interacting bHLH-family transcription factors that play pivotal roles in modulating plant growth and development, by directly binding to their promoters to induce their gene expression, and by inhibiting their interaction with phyB in the light. Moreover, our data demonstrate that CBF1 promotes PIF4/PIF5 protein accumulation and hypocotyl growth at both 22°C and 17°C, but not at 4°C, with a more prominent role at 17°C than at 22°C. Together, our study reveals that CBF1 integrates light and temperature control of hypocotyl growth by promoting PIF4 and PIF5 protein abundance in the light, thus providing insights into the integration mechanisms of light and temperature signaling pathways in plants.

A novel model for predicting prognosis and response to immunotherapy in nasopharyngeal carcinoma patients.

Blood-based biomarkers of immune checkpoint inhibitors (ICIs) response in patients with nasopharyngeal carcinoma (NPC) are lacking, so it is necessary to identify biomarkers to select NPC patients who will benefit most or least from ICIs. The absolute values of lymphocyte subpopulations, biochemical indexes, and blood routine tests were determined before ICIs-based treatments in the training cohort (n = 130). Then, the least absolute shrinkage and selection operator (Lasso) Cox regression analysis was developed to construct a prediction model. The performances of the prediction model were compared to TNM stage, treatment, and Epstein-Barr virus (EBV) DNA using the concordance index (C-index). Progression-free survival (PFS) was estimated by Kaplan-Meier (K-M) survival curve. Other 63 patients were used for validation cohort. The novel model composed of histologic subtypes, CD19+ B cells, natural killer (NK) cells, regulatory T cells, red blood cells (RBC), AST/ALT ratio (SLR), apolipoprotein B (Apo B), and lactic dehydrogenase (LDH). The C-index of this model was 0.784 in the training cohort and 0.735 in the validation cohort. K-M survival curve showed patients with high-risk scores had shorter PFS compared to the low-risk groups. For predicting immune therapy responses, the receiver operating characteristic (ROC), decision curve analysis (DCA), net reclassifcation improvement index (NRI) and integrated discrimination improvement index (IDI) of this model showed better predictive ability compared to EBV DNA. In this study, we constructed a novel model for prognostic prediction and immunotherapeutic response prediction in NPC patients, which may provide clinical assistance in selecting those patients who are likely to gain long-lasting clinical benefits to anti-PD-1 therapy.

14-3-3 proteins regulate photomorphogenesis by facilitating light-induced degradation of PIF3.

14-3-3s are highly conserved phosphopeptide-binding proteins that play important roles in various developmental and signaling pathways in plants. However, although protein phosphorylation has been proven to be a key mechanism for regulating many pivotal components of the light signaling pathway, the role of 14-3-3 proteins in photomorphogenesis remains largely obscure. PHYTOCHROME-INTERACTING FACTOR3 (PIF3) is an extensively studied transcription factor repressing photomorphogenesis, and it is well-established that upon red (R) light exposure, photo-activated phytochrome B (phyB) interacts with PIF3 and induces its rapid phosphorylation and degradation. PHOTOREGULATORY PROTEIN KINASES (PPKs), a family of nuclear protein kinases, interact with phyB and PIF3 in R light and mediate multisite phosphorylation of PIF3 in vivo. Here, we report that two members of the 14-3-3 protein family, 14-3-3λ and κ, bind to a serine residue in the bHLH domain of PIF3 that can be phosphorylated by PPKs, and act as key positive regulators of R light-induced photomorphogenesis. Moreover, 14-3-3λ and κ preferentially interact with photo-activated phyB and promote the phyB-PIF3-PPK complex formation, thereby facilitating phyB-induced phosphorylation and degradation of PIF3 upon R light exposure. Together, our data demonstrate that 14-3-3λ and κ work in close concert with the phyB-PIF3 module to regulate light signaling in Arabidopsis.

Shape and Shear Stress Impact on the Toxicity of Mesoporous Silica Nanoparticles: In Vitro and In Vivo Evidence.

Mesoporous silica nanoparticles (MSNs) are widely used in the biomedical field because of their unique and excellent properties. However, the potential toxicity of different shaped MSNs via injection has not been fully studied. This study aims to systematically explore the impact of shape and shear stress on the toxicity of MSNs after injection. An in vitro blood flow model was developed to investigate the cytotoxicity and the underlying mechanisms of spherical MSNs (S-MSN) and rodlike MSNs (R-MSN) in human umbilical vein endothelial cells (HUVECs). The results suggested that the interactions between MSNs and HUVECs under the physiological flow conditions were significantly different from that under static conditions. Whether under static or flow conditions, R-MSN showed better cellular uptake and less oxidative damage than S-MSN. The main mechanism of cytotoxicity induced by R-MSN was due to shear stress-dependent mechanical damage of the cell membrane, while the toxicity of S-MSN was attributed to mechanical damage and oxidative damage. The addition of fetal bovine serum (FBS) alleviated the toxicity of S-MSN by reducing cellular uptake and oxidative stress under static and flow conditions. Moreover, the in vivo results showed that both S-MSN and R-MSN caused cardiovascular toxicity in zebrafish and mouse models due to the high shear stress, especially in the heart. S-MSN led to severe oxidative damage at the accumulation site, such as liver, spleen, and lung in mice, while R-MSN did not cause significant oxidative stress. The results of in vitro blood flow and in vivo models indicated that particle shape and shear stress are crucial to the biosafety of MSNs, providing new evidence for the toxicity mechanisms of the injected MSNs.

Cascaded parallel crowd counting network with multi-resolution collaborative representation.

Accurately estimating the size and density distribution of a crowd from images is of great importance to public safety and crowd management during the COVID-19 pandemic, but it is very challenging as it is affected by many complex factors, including perspective distortion and background noise information. In this paper, we propose a novel multi-resolution collaborative representation framework called the cascaded parallel network (CP-Net), consisting of three parallel scale-specific branches connected in a cascading mode. In the framework, the three cascaded multi-resolution branches efficiently capture multi-scale features through their specific receptive fields. Additionally, multi-level feature fusion and information filtering are performed continuously on each branch to resist noise interference and perspective distortion. Moreover, we design an information exchange module across independent branches to refine the features extracted by each specific branch and deal with perspective distortion by using complementary information of multiple resolutions. To further improve the robustness of the network to scale variance and generate high-quality density maps, we construct a multi-receptive field fusion module to aggregate multi-scale features more comprehensively. The performance of our proposed CP-Net is verified on the challenging counting datasets (UCF_CC_50, UCF-QNRF, Shanghai Tech A&B, and WorldExpo'10), and the experimental results demonstrate the superiority of the proposed method.

Multiple Stimuli-Responsive Luminescent Chiral Hybrid Antimony Chlorides for Anti-Counterfeiting and Encryption Applications.

Stimuli-responsive circularly polarized luminescence (CPL) materials are ideal for information anti-countering applications, but the best-performing materials have not yet been identified. This work presents enantiomorphic hybrid antimony halides R-(C5 H12 NO)2 SbCl5 (1) and S-(C5 H12 NO)2 SbCl5 (2) showing mirror-imaged CPL activity with a dissymmetry factor of 1.2×10-3 . Interestingly, the DMF-induced structural transformation is realized to obtain non-emissive R-(C5 H12 NO)2 SbCl5 ⋅ DMF (3) and S-(C5 H12 NO)2 SbCl5 ⋅ DMF (4) upon exposure to DMF vapor. The transformation process is reversed upon heating. DFT calculations showed that the DMF-induced-quenched-luminescence is attributed to the intersection of the ground and excited state curves on the configuration coordinates. Unexpectedly, the nanocrystals of the chiral antimony halides 1 and 2 were prepared and indicate the excellent solution process performance. The reversible PL and CPL switching gives the system applications in information technology, anti-counterfeiting, encryption-decryption, and logic gates.

Cyclodextrin-Derived ROS-Generating Nanomedicine with pH-Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy.

Nowadays, destruction of redox homeostasis to induce cancer cell death is an emerging anti-cancer strategy. Here, the authors utilized pH-sensitive acetalated ß-cyclodextrin (Ac-ß-CD) to efficiently deliver dihydroartemisinin (DHA) for tumor ferroptosis therapy and chemodynamic therapy in a synergistic manner. The Ac-ß-CD-DHA based nanoparticles are coated by an iron-containing polyphenol network. In response to the tumor microenvironment, Fe2+ /Fe3+ can consume glutathione (GSH) and trigger the Fenton reaction in the presence of hydrogen peroxide (H2 O2 ), leading to the generation of lethal reactive oxygen species (ROS). Meanwhile, the OO bridge bonds of DHA are also disintegrated to enable ferroptosis of cancer cells. Their results demonstrate that these nanoparticles acted as a ROS generator to break the redox balance of cancer cells, showing an effective anticancer efficacy, which is different from traditional approaches.

Hinge region of Arabidopsis phyA plays an important role in regulating phyA function.

Phytochrome A (phyA) is the only plant photoreceptor that perceives far-red light and then mediates various responses to this signal. Phosphorylation and dephosphorylation of oat phyA have been extensively studied, and it was shown that phosphorylation of a serine residue in the hinge region of oat phyA could regulate the interaction of phyA with its signal transducers. However, little is known about the role of the hinge region of Arabidopsis phyA. Here, we report that three sites in the hinge region of Arabidopsis phyA (i.e., S590, T593, and S602) are essential in regulating phyA function. Mutating all three of these sites to either alanines or aspartic acids impaired phyA function, changed the interactions of mutant phyA with FHY1 and FHL, and delayed the degradation of mutant phyA upon light exposure. Moreover, the in vivo formation of a phosphorylated phyA form was greatly affected by these mutations, while our data indicated that the abundance of this phosphorylated phyA form correlated well with the extent of phyA function, thus suggesting a pivotal role of the phosphorylated phyA in inducing the far-red light response. Taking these data together, our study reveals the important role of the hinge region of Arabidopsis phyA in regulating phyA phosphorylation and function, thus linking specific residues in the hinge region to the regulatory mechanisms of phyA phosphorylation.

Insight into the Dissolution Molecular Mechanism of Ternary Solid Dispersions by Combined Experiments and Molecular Simulations.

With the increase concern of solubilization for insoluble drug, ternary solid dispersion (SD) formulations developed more rapidly than binary systems. However, rational formulation design of ternary systems and their dissolution molecular mechanism were still under development. Current research aimed to develop the effective ternary formulations and investigate their molecular mechanism by integrated experimental and modeling techniques. Glipizide (GLI) was selected as the model drug and PEG was used as the solubilizing polymer, while surfactants (e.g., SDS or Tween80) were the third components. SD samples were prepared at different weight ratio by melting method. In the dissolution tests, the solubilization effect of ternary system with very small amount of surfactant (drug/PEG/surfactant 1/1/0.02) was similar with that of binary systems with high polymer ratios (drug/PEG 1/3 and 1/9). The molecular structure of ternary systems was characterized by differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), X-ray diffraction (XRD), and scanning electron microscope (SEM). Moreover, molecular dynamic (MD) simulations mimicked the preparation process of SDs, and molecular motion in solvent revealed the dissolution mechanism of SD. As the Gordon-Taylor equation described, the experimental and calculated values of Tg were compared for ternary and binary systems, which confirmed good miscibility of GLI with other components. In summary, ternary SD systems could significantly decrease the usage of polymers than binary system. Molecular mechanism of dissolution for both binary and ternary solid dispersions was revealed by combined experiments and molecular modeling techniques. Our research provides a novel pathway for the further research of ternary solid dispersion formulations.

Analysis of the Literature and Patents on Solid Dispersions from 1980 to 2015.

Background: Solid dispersions are an effective formulation technique to improve the solubility, dissolution rate, and bioavailability of water-insoluble drugs for oral delivery. In the last 15 years, increased attention was focused on this technology. There were 23 marketed drugs prepared by solid dispersion techniques. Objective: This study aimed to report the big picture of solid dispersion research from 1980 to 2015. Method: Scientific knowledge mapping tools were used for the qualitative and the quantitative analysis of patents and literature from the time and space dimensions. Results: Western Europe and North America were the major research areas in this field with frequent international cooperation. Moreover, there was a close collaboration between universities and industries, while research collaboration in Asia mainly existed between universities. The model drugs, main excipients, preparation technologies, characterization approaches and the mechanism involved in the formulation of solid dispersions were analyzed via the keyword burst and co-citation cluster techniques. Integrated experimental, theoretical and computational tools were useful techniques for in silico formulation design of the solid dispersions. Conclusions: Our research provided the qualitative and the quantitative analysis of patents and literature of solid dispersions in the last three decades.

Stereoselective Synthesis of Polycycles Containing an Aziridine Group: Intramolecular aza-Diels-Alder Reactions of Unactivated 2H-Azirines with Unactivated Dienes.

Vinyl azide with a pendent diene can undergo thermal decomposition to a related azirine intermediate, which was used immediately in an intramolecular aza-Diels-Alder reaction to furnish an aziridine-containing trans-fused tricyclic core structure with excellent stereoselectivity. The method provides a facile entry to complex polycyclic alkaliods which can be further elaborated by ring-opening reactions and ring expansion of the aziridine moiety, as well as by dihydroxylation of the alkene group.

Protective effect of astaxanthin on ANCA-associated vasculitis.

OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by inflammation and fibrinoid necrosis of medium and small vessels, and its pathogenesis is closely related to inflammation and oxidative stress. Astaxanthin (ATX) is a carotenoid with anti-inflammatory, antioxidant, and immunomodulatory effects. We hypothesized that ATX could play a role in AAV treatment. This study aimed to investigate whether ATX has a protective effect against AAV and to elucidate its regulatory mechanism. METHODS: In vitro experiments, neutrophils isolated from healthy people were treated with ATX or not and cultured with serum from myeloperoxidase (MPO) -ANCA-positive patients and healthy persons. The levels of IL-6 and TNF-α in neutrophil culture supernatant before and after stimulation were measured. Neutrophil extracellular traps (NETs) and intracellular reactive oxygen species (ROS) in neutrophils were detected after stimulation. In vivo study, experimental autoimmune vasculitis (EAV) rat models were established and then treated with ATX via intragastric administration for 6 consecutive weeks. Urinary erythrocytes, urinary proteins, and serum creatinine were detected and HE staining was performed to assess renal injury in rats. Lung hemorrhage was observed by gross dissection and microscopic Prussian blue staining. The level of serum MPO-ANCA was detected. Serum IL-6, TNF-α, superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) in rats were measured to explore the effects of ATX on oxidative stress and inflammation in EAV rats. The deposition of MPO in kidney and lung of rats was detected by immunohistochemistry. RESULTS: ATX significantly inhibited neutrophil secretion of inflammatory factors IL-6 and TNF-α. ATX reduced the elevated levels of ROS in neutrophils stimulated by serum from AAV patients and alleviated the release of NETs. ATX administration was observed to reduce the degree of hematuria, proteinuria, and glomerular crescent formation in EAV rats. The degree of pulmonary hemorrhage was significantly reduced. Besides, the serum levels of IL-6 and TNF-α were attenuated, and antioxidant SOD and GSH-px increased in serum. Pathological results showed that MPO deposition was decreased in lung and kidney tissues after ATX treatment. CONCLUSION: ATX could ameliorate the organ damages in EAV rats. It could serve as a hopeful therapy for AAV by its anti-inflammatory and anti-oxidative feature as a unique nature carotenoid.

Synthetic Biomimetic Liposomes Harness Efferocytosis Machinery for Highly Efficient Macrophages-Targeted Drug Delivery to Alleviate Inflammation.

Macrophages play pivotal roles in the regulation of inflammatory responses and tissue repair, making them a prime target for inflammation alleviation. However, the accurate and efficient macrophages targeting is still a challenging task. Motivated by the efficient and specific removal of apoptotic cells by macrophages efferocytosis, a novel biomimetic liposomal system called Effero-RLP (Efferocytosis-mediated Red blood cell hybrid Liposomes) is developed which incorporates the membrane of apoptotic red blood cells (RBCs) with liposomes for the purpose of highly efficient macrophages targeting. Rosiglitazone (ROSI), a PPARγ agonist known to attenuate macrophage inflammatory responses, is encapsulated into Effero-RLP as model drug to regulate macrophage functions in DSS-induced colitis mouse model. Intriguingly, the Effero-RLP exhibits selective and efficient uptake by macrophages, which is significantly inhibited by the efferocytosis blocker Annexin V. In animal models, the Effero-RLP demonstrates rapid recognition by macrophages, leading to enhanced accumulation at inflammatory sites. Furthermore, ROSI-loaded Effero-RLP effectively alleviates inflammation and protects colon tissue from injury in the colitis mouse model, which is abolished by deletion of macrophages from mice model. In conclusion, the study highlights the potential of macrophage targeting using efferocytosis biomimetic liposomes. The development of Effero-RLP presents novel and promising strategies for alleviating inflammation.

Predicting liposome formulations by the integrated machine learning and molecular modeling approaches.

Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability. Due to the complex formulation components and preparation process, formulation screening mostly relies on trial-and-error process with low efficiency. Here liposome formulation prediction models have been built by machine learning (ML) approaches. The important parameters of liposomes, including size, polydispersity index (PDI), zeta potential and encapsulation, are predicted individually by optimal ML algorithm, while the formulation features are also ranked to provide important guidance for formulation design. The analysis of key parameter reveals that drug molecules with logS [-3, -6], molecular complexity [500, 1000] and XLogP3 (≥2) are priority for preparing liposome with higher encapsulation. In addition, naproxen (NAP) and palmatine HCl (PAL) represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability. The consistency between predicted and experimental value verifies the satisfied accuracy of ML models. As the drug properties are critical for liposome particles, the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations. The modeling structure reveals that NAP molecules could distribute into lipid layer, while most PAL molecules aggregate in the inner aqueous phase of liposome. The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations. In summary, the general prediction models are built to predict liposome formulations, and the impacts of key factors are analyzed by combing ML with molecular modeling. The availability and rationality of these intelligent prediction systems have been proved in this study, which could be applied for liposome formulation development in the future.