Amylose molecular weight affects the complexing state and digestibility of the resulting starch-lipid complexes.

Previous RS5 (type 5 resistant starch) research has significantly broadened starch use and benefited society, yet the effects of the molecular weight of amylose on RS5 remain underexplored. In this study, amyloses with different molecular weights were complexed with caproic acid (C6), lauric acid (C12), and stearic acid (C18) to observe the effects of the molecular weight of amylose on the structure and in vitro digestive properties of RS5. Gel permeation chromatography revealed that the peak average molecular weight (Mp) values of high-amylose cornstarch NF-CGK (CGK), high-amylose cornstarch obtained via cornstarch via autoclave (high temperature and high pressure)-cooling combined pullulanase enzymatic hydrolysis (CTE), and high-amylose cornstarch NF-G370 (HCK) were 21,282, 171,537, and 188,084 before fatty acid complexation, respectively. Additionally, their weight average molecular weight (Mw) values of 32,429, 327,344, and 410,610 and hydrolysis rates of 58.12 %, 86.77 %, and 64.58 %, respectively. The hydrolysis rate of low-Mw amylose (GCK) complexes with fatty acids was lower than that of HCK and CTE starch-lipid complexes. However, HCK and CTE having similar molecular weights, there was no significant difference in the hydrolysis rate of starch-lipid complexes. X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy and complexing index analyses confirmed the formation of these complexes. This study proposed the mechanism of RS5 formation and provided guidance for its future development.

Key structural factors that determine the in vitro enzymatic digestibility of amylose-complexes.

The effects of complexing conditions on the formation of amylose-lipid-protein complexes and relationships between structure and digestion of amylose-lipid and amylose-lipid-protein complexes were poorly understood. The objective of this study was to investigate the effects of complexing time (0, 0.5, 2, 4 and 6 h) and temperature (60, 70, 80, 90 and 100 °C) on the structure and in vitro amylolysis of amylose-lauric acid (AM-LA) and amylose-lauric acid-ß-lactoglobulin (AM-LA-ßLG) complexes, and to understand the relationships between structure and in vitro digestiblity of these complexes. Longer complexing time and higher complexing temperature promoted the formation of greater amounts of the more stable type II crystallites than type I crystallites in both AM-LA and AM-LA-ßLG complexes, which in turn decreased the rate and extent of the complexes digestion to a greater extent. Correlation analyses between parameters for structure and digestion kinetics showed that both the quantity of AM-LA and AM-LA-ßLG complexes and the quality of their arrangement into V-type crystallites influenced their rate and extent of digestion. This study demonstrates that AM-LA and AM-LA-ßLG complexes can be prepared with designed structural and functional properties tailored for various applications.

Effects of fatty acids and glycerides on the structure, cooking quality, and in vitro starch digestibility of extruded buckwheat noodles.

This study aimed to explore the effects of various lipids on the structure, cooking quality, and in vitro starch digestibility of extruded buckwheat noodles (EBNs) with and without 20% high-amylose corn starch (HACS). Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction revealed that lauric acid bound more strongly to starch than did stearic acid and oleic acid, and the binding capacity of fatty acids with starch was stronger than that of glycerides. The presence of HACS during extrusion facilitated increased formation of starch-lipid complexes. Evaluations of cooking quality and digestion characteristics showed that EBNs containing 20% HACS and 0.5% glycerol monooleate demonstrated the lowest cooking loss (7.28%), and that with 20% HACS and 0.5% oleic acid displayed the lowest predicted glycemic index (pGI) (63.54) and highest resistant starch (RS) content (51.64%). However, excessive starch-lipid complexes were detrimental to EBNs cooking quality and the resistance of starch to digestive enzymes because of the damage to the continuity of the starch gel network. This study establishes a fundamental basis for the development of EBNs with superior cooking quality and a relatively lower GI.

Hydrophobic deep eutectic solvent (HDES) as oil phase in lipid-based drug formulations.

There is increasing pharmaceutical interest in deep eutectic solvents not only as a green alternative to organic solvents in drug manufacturing, but also as liquid formulation for drug delivery. The present work introduces a hydrophobic deep eutectic solvent (HDES) to the field of lipid-based formulations (LBF). Phase behavior of a mixture with 2:1 M ratio of decanoic- to dodecanoic acid was studied experimentally and described by thermodynamic modelling. Venetoclax was selected as a hydrophobic model drug and studied by atomistic molecular dynamics simulations of the mixtures. As a result, valuable molecular insights were gained into the interaction networks between the different components. Moreover, experimentally the HDES showed greatly enhanced drug solubilization compared to conventional glyceride-based vehicles, but aqueous dispersion behavior was limited. Hence surfactants were studied for their ability to improve aqueous dispersion and addition of Tween 80 resulted in lowest droplet sizes and high in vitro drug release. In conclusion, the combination of HDES with surfactant(s) provides a novel LBF with high pharmaceutical potential. However, the components must be finely balanced to keep the integrity of the solubilizing HDES, while enabling sufficient dispersion and drug release.

Therapeutic impacts of GNE­477­loaded H2O2 stimulus­responsive dodecanoic acid­phenylborate ester­dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer­associated death in young people. GNE­477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus­responsive dodecanoic acid (DA)­phenylborate ester­dextran (DA­B­DEX) polymeric micelle delivery system for GNE­477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE­477 loaded DA­B­DEX (GNE­477@DBD) tumor­targeting drug delivery system was established and the release of GNE­477 was measured. The cellular uptake of GNE­477@DBD by three OS cell lines (MG­63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA­B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA­B­DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE­477@DBD by cells with sustained release of GNE­477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT­qPCR, demonstrated that GNE­477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE­477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2­responsive DA­B­DEX presents a promising delivery system for hydrophobic anti­tumor drugs for OS therapy.

Near-Infrared Responsive Nanocomposite Hydrogel Dressing with Anti-Inflammation and Pro-Angiogenesis for Wound Healing.

Anti-inflammatory and angiogenesis are two important factors in wound healing. Wound dressings with anti-inflammation and vascularization are essential to address complex interventions, expensive treatments, and uncontrolled release mechanisms. Based on the above considerations, we designed a near-infrared (NIR)-responsive hydrogel dressing, which is composed of mPDA-DFO@LA nanoparticles (mPDA: dopamine hydrochloride nanoparticles, DFO: deferoxamine, LA: lauric acid), valsartan (abbreviated as Va), and dopamine-hyaluronic acid hydrogel. The hydrogel dressing demonstrated injectability, bioadhesive, and photothermal properties. The results indicated the obtained dressing by releasing Va can appropriately regulate macrophage phenotype transformation from M1 to M2, resulting in an anti-inflammatory environment. In addition, DFO encapsulated by LA can be sustainably released into the wound site by NIR irradiation, which further prevents excessive neovascularization. Notably, the results in vivo indicated the mPDA-DFO@LA/Va hydrogel dressing significantly enhanced wound recovery, achieving a healing rate of up to 96% after 11 days of treatment. Therefore, this NIR-responsive hydrogel dressing with anti-inflammation, vascularization, and on-demand programmed drug release will be a promising wound dressing for wound infection.

Effect of electron beam irradiation pretreatment and different fatty acid types on the formation, structural characteristics and functional properties of starch-lipid complexes.

The effects of different electron beam irradiation doses (2, 4, 8 KGy) and various types of fatty acids (lauric acid, stearic acid, and oleic acid) on the formation, structure, physicochemical properties, and digestibility of starch-lipid complex were investigated. The complexing index of the complexes was higher than 85 %, indicating that the three fatty acids could easily form complexes with starch. With the increase of electron beam irradiation dose, the complexing index increased first and then decreased. The highest complexing index was lauric acid (97.12 %), stearic acid (96.80 %), and oleic acid (97.51 %) at 2 KGy radiation dose, respectively. Moreover, the microstructure, crystal structure, thermal stability, rheological properties, and starch solubility were analyzed. In vitro digestibility tests showed that adding fatty acids could reduce the content of hydrolyzed starch, among which the resistant starch content of the starch-oleic acid complex was the highest (54.26 %). The lower dose of electron beam irradiation could decrease the digestibility of starch and increase the content of resistant starch.

Study on multiscale structures and digestibility of cassava starch and medium-chain fatty acids complexes using molecular simulation techniques.

Effect of complexation of three medium-chain fatty acids (octanoic, decylic and lauric acid, OA, DA and LA, respectively) on structural characteristics, physicochemical properties and digestion behaviors of cassava starch (CS) was investigated. Current study indicated that LA was more easily to combine with CS (complex index 88.9%), followed by DA (80.9%), which was also consistent with their corresponding complexed lipids content. Following the investigation of morphology, short-range ordered structure, helical structure, crystalline/amorphous region and fractal dimension of the various complexes, all cassava starch-fatty acids complexes (CS-FAs) were characterized with a flaked morphology rather than a round morphology in native starch (control CS). X-ray diffraction demonstrated that all CS-FAs had a V-type crystalline structure, and nuclear magnetic resonance spectroscopy confirmed that the complexes made from different fatty acids displayed similar V6 or V7 type polymorphs. Interestingly, small-angle X-ray scattering analysis revealed that α value became greater following increased carbon chain length of fatty acids, indicating the formation of a more ordered fractal structure in the aggregates. Changes in rheological parameters G' and G'' indicated that starch complexed with fatty acids was more likely to form a gel network, but difference among three CS-FAs complexes was significant, which might be contributed to their corresponding hydrophobicity and hydrophilicity raised from individual fatty acids. Importantly, digestion indicated that CS-LA complexes had the lowest hydrolysis degree, followed by the greatest RS content, indicating the importance of chain length of fatty acids for manipulating the fine structure and functionality of the complexes.

Effect of lecithin on the complexation between different botanically sourced starches and lauric acid.

This research investigated the effect of lecithin on the complexation of lauric acid with maize starch, potato starch, waxy maize starch, and high amylose maize starch. Rapid visco analysis showed that lecithin altered the setback pattern of potato starch-lauric acid and maize starch-lauric acid mixtures but not waxy maize starch-lauric acid. Further investigation, including differential scanning calorimetry, complex index, and X-ray diffraction, showed that lecithin enhanced the complexation of maize starch, potato starch, and high amylose maize starch with lauric acid. Fourier transform infrared and Raman spectroscopy revealed increasingly ordered structures formed in maize starch-lauric acid-lecithin, potato starch-lauric acid-lecithin, and high amylose maize starch-lauric acid-lecithin systems compared to corresponding binary systems. These highly ordered complexes of maize starch, potato starch, and high amylose maize starch also demonstrated greater resistance to in vitro enzymatic hydrolysis. Waxy maize starch complexation however remained unaffected by lecithin. The results of this study show that lecithin impacts complexation between fatty acids and native starches containing amylose, with the starch source being critical. Lecithin minimally impacted the complexation of low amylose starch and fatty acids.

Comparative study on the structure characterization and activity of RS5 made from Canna edulis native starch and high-amylose corn starch.

In this study, the high amylose corn starch and Canna edulis native starch were compounded with lauric acid and fermented by human fecal inoculation in vitro. Changes in beneficial metabolite profile and microbiota composition were evaluated. The structural properties showed that both NS-12C and HAMS-12C formed V-shaped crystals under the same preparation method, but NS-12C had a higher composite index and resistance content than HAMS-12C. At the end of fermentation, the starch-lauric acid complexes prepared from the two types of starch significantly promoted the formation of short-chain fatty acids and the contents of acetic acid, butyric acid and valeric acid produced by NS-12C were higher than those of HAMS-12C(p>0.05). HAMS-12C and NS-12C both increased the relative abundance of Blautia. Notably, NS-12C also increased the relative abundance of beneficial bacteria Bifidobacterium and Meganomas, while HAMS-12C did not. These results suggested that this effect may be related to starch type and provide a basis for designing and producing functional foods to improve intestinal health in Canna edulis native starch.

Engineering lauric acid-based nanodrug delivery systems for restoring chemosensitivity and improving biocompatibility of 5-FU and OxPt against Fn-associated colorectal tumor.

Colorectal cancer (CRC) occurs in the colorectum and ranks second in the global incidence of all cancers, accounting for one of the highest mortalities. Although the combination chemotherapy regimen of 5-fluorouracil (5-FU) and platinum(IV) oxaliplatin prodrug (OxPt) is an effective strategy for CRC treatment in clinical practice, chemotherapy resistance caused by tumor-resided Fusobacterium nucleatum (Fn) could result in treatment failure. To enhance the efficacy and improve the biocompatibility of combination chemotherapy, we developed an antibacterial-based nanodrug delivery system for Fn-associated CRC treatment. A tumor microenvironment-activated nanomedicine 5-FU-LA@PPL was constructed by the self-assembly of chemotherapeutic drug derivatives 5-FU-LA and polymeric drug carrier PPL. PPL is prepared by conjugating lauric acid (LA) and OxPt to hyperbranched polyglycidyl ether. In principle, LA is used to selectively combat Fn, inhibit autophagy in CRC cells, restore chemosensitivity of 5-FU as well as OxPt, and consequently enhance the combination chemotherapy effects for Fn-associated drug-resistant colorectal tumor. Both in vitro and in vivo studies exhibited that the tailored nanomedicine possessed efficient antibacterial and anti-tumor activities with improved biocompatibility and reduced non-specific toxicity. Hence, this novel anti-tumor strategy has great potential in the combination chemotherapy of CRC, which suggests a clinically relevant valuable option for bacteria-associated drug-resistant cancers.

Anticancer potential of thiocolchicoside and lauric acid loaded chitosan nanogel against oral cancer cell lines: a comprehensive study.

The present study explored the anticancer activity of a Chitosan-based nanogel incorporating thiocolchicoside and lauric acid (CTL) against oral cancer cell lines (KB-1). Cell viability, AO/EtBr dual staining and Cell cycle analysis were done to evaluate the impact of CTL nanogel on oral cancer cells. Real-time PCR was performed to analyze proapoptotic and antiapoptotic gene expression in CTL-treated KB-1 cells. Further, molecular docking analysis was conducted to explore the interaction of our key ingredient, thiocolchicoside and its binding affinities. The CTL nanogel demonstrated potent anticancer activity by inhibiting oral cancer cell proliferation and inducing cell cycle arrest in cancer cells. Gene expression analysis indicated alterations in Bax and Bcl-2 genes; CTL nanogel treatment increased Bax mRNA expression and inhibited the Bcl-2 mRNA expression, which showed potential mechanisms of the CTL nanogel's anticancer action. It was found that thiocolchicoside can stabilize the protein's function or restore it as a tumour suppressor. The CTL nanogel exhibited excellent cytotoxicity and potent anticancer effects, making it a potential candidate for non-toxic chemotherapy in cancer nanomedicine. Furthermore, the nanogel's ability to modulate proapoptotic gene expression highlights its potential for targeted cancer therapy. This research contributes to the growing interest in Chitosan-based nanogels and their potential applications in cancer treatment.

Thermal performance enhancement of lauric acid using nanomaterials as composite phase change material.

In the present work, lauric acid was taken as a phase change material (PCM), and different nanoparticles (NPs) such as SiO2, TiO2, CuO, and ZnO were taken as the supporting materials. CuO NPs were prepared through the co-precipitation technique; SiO2, TiO2, and ZnO NPs were synthesized via the sol-gel technique. These NPs with different weight fractions were dispersed into molten lauric acid, individually. The variations in thermal properties (phase change temperature and latent heat for solid and liquid) of the prepared composite PCMs due to the dispersion of NPs were observed by DSC analyses. An increase in thermal conductivity of the composite PCMs was observed with the increasing weight fraction of NPs. In order to ascertain the long-term utility, a thermal reliability test was conducted on the composite PCMs with repeated heating and cooling cycles. Also, the specific heats of the pure PCM and the composite PCMs were determined as a function of temperature. Further, the experimental investigation was performed on the pure PCM and the prepared composite PCMs to assess their phase change behavior, and the test results clearly proved that the time required for the complete melting and freezing process of the composite PCMs was less when compared to pure PCM. By considering the above facts, the newly prepared composite PCMs can be recommended as a potential candidate for low-temperature solar heating applications.

The influence of short-range molecular order in gelatinized starch on the formation of starch-lauric acid complexes.

A model system of gelatinized wheat starch (GWS) and lauric acid (LA) was used to examine the effect of residual short-range molecular order in GWS on the formation of starch-lipid complexes. The extent of residual short-range molecular order, as determined by Raman spectroscopy, decreased with increasing water content or heating duration of gelatinization. The enthalpy changes, crystallinity, short-range molecular order and the in vitro enzymic digestion of GWS-LA complexes increased initially to a maximum and then declined as the short-range molecular order in GWS decreased, showing that there was an optimal amount of residual short-range molecular order in GWS for maximizing GWS-LA complexes formation. Below this optimum amount, the limited disruption of short-range molecular order may constrain the mobility of amylose chains for complexation with LA, whereas with excessive disruption above this amount the amylose chains may be too disorganized or entangled to form complexes with LA. The susceptibility of GWS-LA complexes to enzymatic hydrolysis was influenced by both long- and short-range structural order, and to a lesser extent the amounts of complexes. This study showed clearly the role of short-range molecular order in gelatinized starch in influencing the formation of GWS-LA complexes.

Micelle Formation of Dodecanoic Acid with Alkali Metal Counterions.

Alkali series with different atomic numbers affect the physicochemical properties of aqueous solutions. The micellar properties of aqueous solutions of dodecanoate as surfactants were measured by changing the counterions (C12-Na, C12-K, C12-Rb, and C12-Cs). A plot of Krafft temperature vs. alkali metal atomic number showed a downward convex curve, with its minimum temperature (20°C) in the C12-K system. By contrast, a plot of the critical micelle concentration (CMC) vs. alkali metal atomic number exhibited an upward convex curve with the maximum CMC (25.6 mmol L-1) at C12-K. Furthermore, the minimum surface tension (γ min ) of the solution at the CMC increased with increasing atomic number (C12-Na ≈ C12-K < C12-Rb < C12-Cs). The size of the dodecanoate micelles decreased with increasing atomic number. The ionization degree of the micelles also increased with increasing atomic number of the alkali metal. Small-angle X-ray scattering (SAXS) measurements revealed that alkali dodecanoate micelles formed spherical to ellipsoidal structures. In addition, micelles from the shell region showed large electrostatic repulsion, judging from the shape of the spectrum in the higher Q -1 region. From the measurement results of the solubilization of naphthalene into the micelles, the size of the micelles corresponded to the maximum solubilization quantity of naphthalene.

Preferential Removal of Alkali Metal Using Dodecanoic Acid and Sodium Dodecyl Sulfate in Foam Separation System.

The selectivity of adsorption between alkali metal ions (Li+, Na+, K+, Rb+, and Cs+) based on the ionic functional groups of the surfactants was studied using two types of surfactants, dodecanoic acid (DA) and sodium dodecyl sulfate (SDS), in the foam separation system. The results showed that Li+ was preferably removed by foam separation using DA. The removal rates of other alkali metal ions were relatively low, and there were no significant differences among other alkali metal ions (Na+, K+, Rb+, and Cs+). However, Cs+ exhibited the highest removal rate among the mixed alkali metals by foam separation using SDS. From these results, the selectivity of the alkali metal in foam separation was dependent on the type of surfactant.

Can Photothermal Post-Operative Cancer Treatment Be Induced by a Thermal Trigger?

One of the current challenges in the post-operative treatment of breast cancer is to develop a local therapeutic vector for preventing recurrence and metastasis. Herein, we develop a core-shell fibrous scaffold comprising phase-change materials and photothermal/chemotherapy agents, as a thermal trigger for programmable-response drug release and synergistic treatment. The scaffold is obtained by in situ growth of a zeolitic imidazolate framework-8 (ZIF-8) shell on the surface of poly(butylene succinate)/lauric acid (PBS/LA) phase-change fibers (PCFs) to create PCF@ZIF-8. After optimizing the core-shell and phase transition behavior, gold nanorods (GNRs) and doxorubicin hydrochloride (DOX) co-loaded PCF@ZIF-8 scaffolds were shown to significantly enhance in vitro and in vivo anticancer efficacy. In a healthy tissue microenvironment at pH 7.4, the ZIF-8 shell ensures the sustained release of DOX. If the tumor recurs, the acidic microenvironment induces the decomposition of the ZIF-8 shell. Under the second near-infrared (NIR-II) laser treatment, GNR-induced thermal not only directly destroys the relapsed tumor cells but also accelerates DOX release by inducing the phase transition of LA. Our study sheds light on a well-designed programmable-response trigger, which provides a promising strategy for post-operative recurrence prevention of cancer.

The rate and evenness of the substitutions on hyaluronan grafted by dodecanoic acid influenced by the mixed-solvent composition.

In this work, low molecular weight (17 kDa) hyaluronan was modified by dodecanoyl substituents. The activation of dodecanoic acid was mediated by benzoyl chloride towards the preparation of a mixed anhydride, which reacts in a second step with HA in water mixed with an organic solvent. The effect of the cosolvent was studied and showed an even distribution of substituents and higher reaction rate in water: 1,4-dioxane compared to water:tert-butanol where substituents occupy adjacent positions. The chemical characterization of the prepared derivatives was elucidated by NMR, FTIR spectroscopy, thermal analyses, and gas chromatography, while the distribution of substituents was evaluated by enzymatic degradation. Molecular-dynamics simulations reveal opposite solvent separations around HA and dodecanoyl chains, that is stronger in water:tert-butanol solution. The resulting incompatibility of solvation-shells of the two entities repels the reaction intermediates from the HA chain and drives them towards the already bound substituents, explaining the observed differences in the distribution evenness. Thus, the influence of the solvent on the reaction selectivity is observed by shielding reactive sites around HA. Therefore, a control of the distribution of the substituents was obtained by defining the concentration of HA and used cosolvent.

Complex Micellization Behavior of the Polysorbates Tween 20 and Tween 80.

Polysorbates (PSs, Tweens) are widely used surfactant products consisting of a sorbitan ring connecting up to four ethylene oxide (EO) chains of variable lengths, one or more of which are esterified with fatty acids of variable lengths and saturation degrees. Pharmaceutical applications include the stabilization of biologicals in solutions and the solubilization of poorly water soluble, active ingredients. This study characterizes the complex association behavior of compendial PSs PS20 and PS80, which is fundamentally different from that of single-component surfactants. To this end, a series of demicellization experiments of isothermal titration calorimetry with different PS concentrations are evaluated. Their experiment-dependent heats of titration are converted into a common function of the state of a sample, the micellar enthalpy Qm(c). These functions demonstrate that initial micelles are already present at the lowest concentrations investigated, 2 µM for PS20 and 10 µM for PS80. Initial micelles consist primarily of the surfactant species with the lowest individual critical micelle concentration (cmc). With increasing concentration, the other PS species gradually enter these micelles in the sequence of increasing individual cmc's and hydrophilic-lipophilic balance. Concentration ranges with pronounced slopes of Qm(c) can be tentatively assigned to the uptake of the major components of the PS products. Micellization and the variation of the micelle properties progress up to at least 10 mM PS. That means the published cmc values or ranges of PS20 and PS80 may be related to certain, major components being incorporated into and forming specific micelles but must not be interpreted in terms of an absence of micelles below and constant properties, e.g., the surface activity, of the micelles above these ranges. The micellization enthalpy curves differ quite substantially between PS20 and PS80 and, in a subtler fashion, between individual quality grades such as high purity, pure lauric acid/pure oleic acid, super-refined, and China grade.

Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA.

Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a poly(l-cysteine) block with a thiol group (PCys block), and a cationic poly(aspartate) block grafted with diethylenetriamine (PAsp(DETA) block). The cationic polymers efficiently complexed siRNA into polyplexes, showing a sandwich-like structure with a PAsp(-N=C-PEG) out-layer, a crosslinked PCys interlayer, and a complexing core of siRNA and PAsp(DETA). Low pH-triggered breakage of pH-sensitive imine bonds caused PEG shedding. The disulfide bond-crosslinking and pH-triggered PEG shedding synergistically decreased the polyplexes' size from 75 nm to 26 nm. To neutralize excessive positive charges and introduce the targeting ligand, the polyplexes without a PEG layer were coated with an anionic copolymer modified with the targeting ligand lauric acid. The resulting polyplexes exhibited high transfection efficiency and lysosomal escape capacity. This study provides a promising strategy to engineer the size and surface of polyplexes, allowing long blood circulation and targeted delivery of siRNA.