Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.

Nonsmall cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with MYC oncogene overexpression driving tumor progression and immunosuppression. MYC has been deemed "undruggable" for a long period, and the impact of its silencing on the tumor associated macrophage polarization and circadian rhythm remains unexplored. Here, we developed a lipid nanoparticle (siMYC@Dmix) composed of cytidinyl lipid (DNCA), gemini-like cationic lipid (CLD), and DSPE-PEG2000 for efficient MYC siRNA delivery. In vitro, siMYC@Dmix showed robust cellular uptake, lysosomal escape, and ∼77% MYC mRNA silencing in Lewis Lung Carcinoma (LLC) cells. In vivo, siMYC@Dmix treatment significantly inhibited tumor growth in C57BL/6J mice and induced a profound remodeling of the tumor immune microenvironment. This was characterized by a shift in macrophage polarization toward the M1 phenotype, increased infiltration and cytotoxic function of CD8+ T cells, enhanced natural killer (NK) cell activity, and maturation of dendritic cells (DCs). Crucially, MYC silencing restored the expression of core circadian clock genes. Our findings unveil a promising RNAi-based strategy that concurrently targets MYC-driven tumorigenesis, corrects circadian dysfunction, and reinstates antitumor immunity, presenting a multifaceted therapeutic approach for NSCLC.

The nuclear factor-κB (NF-κB) signaling pathway serves as a critical regulator in tumorigenesis and cancer progression, with IκB kinase β (IKKβ) emerging as a pivotal therapeutic target due to its essential role in NF-κB activation. While siRNA-based gene silencing represents a promising strategy for IKKβ inhibition, current delivery systems, including lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc) conjugates, remain predominantly restricted to hepatic applications. In this study, our novel delivery system composed of nucleotidyl lipid (TPS), peptidyl lipid (CLDA), and its mannosylated derivative lipid (CManDA) has been continuously used for effective extrahepatic siRNA delivery. Our optimized formulation (T/50%L/50%M, TPS:CLDA:CManDA = 21:15.75:15.75, molar ratio to siRNA) demonstrates specific tumor targeting and preferential accumulation in tumor-associated macrophages (TAMs) and malignant cells in Lewis lung carcinoma (LLC) models. Mechanistic investigations reveal that TPS/CLDA/CManDA/siIKKβ mediates dual antitumor effects through: (1) Disruption of amino acid metabolic reprogramming via Myc downregulation and (2) M2-to-M1 macrophage repolarization. Furthermore, combination therapy with siRNA targeting KRASG12D (siG12D) exhibits synergistic efficacy against KRASG12D-mutated colon cancer through enhanced proliferation inhibition and antitumor immune activation. This study not only establishes TPS/CLDA/CManDA as a versatile platform for extrahepatic RNA interference (RNAi) therapeutics but also validates IKKβ inhibition as a strategy to concurrently target tumor metabolism and immunosuppression in KRAS-driven malignancies.

Recently, chiral optical fields (COFs) have garnered significant attention due to their multiple controllable degrees of freedom (DOFs), enabling applications in diverse areas such as optical tweezers, manufacturing, and holographic encryption. However, existing schemes fail to achieve precise control over certain aspects, particularly the fine‐tuning of sidelobes, including their overall shape and structural characteristics, which limits their practical applications. Herein, an approach to achieve fine sculpting of COFs using a modular multilayer annular phase plate (MMAPP) is proposed. By adjusting the number and mode of the annular spiral phase in the two modules of the MMAPP, as well as the axicon phase, the high‐order cross phase, and the low‐order cross phase, the experimental manipulation of nine DOFs of COFs is demonstrated, including the chirality, size, sidelobe number, sidelobe distortion degree, sidelobe segment length, sidelobe segment rotation direction, overall polygonal shape, ellipticity, and rotation angle. The proposed method enhances the modulation capabilities of COFs and gives rise to potential applications in particle manipulation and information encryption.

Hepatocellular carcinoma (HCC) is the most prevalent form of invasive liver cancer, representing over 90% of all liver cancer cases. Currently, there is a lack of targeted therapy for HCC. Insulin-like growth factor 1 receptor (IGF1R) is abnormally expressed in HCC, leading to the malignant proliferation and contributing to the antiapoptosis mechanisms in tumor cells. In this study, small interfering RNAs targeting IGF1R mRNA (siIGF1Rs) have been designed. Additionally, a full 2'-F/2'-OMe modification with partial phosphorothioation was applied to improve the biological properties of these siIGF1Rs. Based on previous research, stable lipid complexes with uniform particle sizes were constructed using cytidinyl lipid DNCA/cationic lipid CLD (Mix) supplemented with DSPE-PEG (siIGF1R/Mix/PEG). The complexes were formed through hydrogen-bonding, π-π stacking, and electrostatic interactions. The siIGF1R/Mix/PEG complex entered the cytoplasm and nucleus of HCC cells, reduced IGF1R mRNA and pre-mRNA levels by over 95% and 50% respectively, further arrested the cell cycle in the S phase, and promoted cell apoptosis. Importantly, siIGF1R/Mix/PEG (0.8 mg/kg, i.v.) selectively accumulated in the tumor, significantly inhibiting tumor growth by 91.31% compared to the naked siRNA group, with slower release and a more prolonged effect.

Nucleic acid drugs can function at the gene level,and have the advantages of simple synthesis,easy modification and high specificity.However,there are many obstacles in transfection and in vivo delivery due to their negative charge,high molecular weight,and hydrophilicity.Lipid nanoparticles(LNPs)can encapsulate siRNA or mRNA through electrostatic interactions and five related drugs have been approved as of April 2025.However,due to the inevitable immunogenicity and hepatosplenic toxicity,most LNP-encapsulated nucleic acid drugs were terminated in the early clinical stage.Nucleos(t)idyl lipids are a class of amphiphilic molecules composed of nucleobases or nucleos(t)idyl heads,linkers and lipid tail chains,which can bind with the bases of nucleic acid drugs through hydrogen bonding and π-π stacking and self-assemble to form nanoparticles or micelles with broad application prospects.In this review,we summarize the research progress in delivery systems of nucleic acid drugs based on nucleos(t)idyl lipids and peptidyl lipids,and discuss their differences with LNP-encapsulated nucleic acid drugs,including structural characterization,molecular dynamics simulation,in vivo distribution,as well as efficacy and safety,so as to provide new ideas for improving the targeting delivery of nucleic acid drugs.

Gene therapy has attracted widespread attention in recent years, and one of the important delivery systems is the LNP. However, many LNPs have potential toxicity and accumulate in the liver. Here, we designed and synthesized a Gemini-type mannosylated peptidyl lipid called CManDA(M), which, in combination with the cytidinyl lipid DNCA(D) and the peptidyl lipid CLD(C) (D/50C/50 M), could transfect siRNA (siG12S) into A549 cells to target and silence the KRASG12S gene. The fluorescence intensity in the tumor area of the D/50C/50 M/Cy5.5-siG12S group increased by approximately 2.5 times. Furthermore, full 2'-F/2'-OMe-modified siG12Ss could also be transfected by D/50C/50 M into cells, resulting in target gene silencing. The tumor weight in the D/50C/50 M/M3 group (1.5 mg/kg, i.v.) was reduced by 50 % after administration in a mouse axillary tumor (A549) model, whereas the tumor bioluminescence intensity was only approximately 30 % of that in the blank group in a mouse orthotopic lung cancer model and showed no significant toxicity. Further studies revealed that the mannose groups of CManDA can be exposed on the nanoparticle surface to bind lectins, and CManDA can also shield the formation of a protein corona and alter the composition of the protein corona, which aids in the enhancement of its active targeting function. CManDA is expected to be a safe and effective helper lipid for tumor-targeted delivery of siRNA in vivo.

NAD(P)H:quinone oxidoreductase-1 (NQO1), a protein highly expressed in tumor cells, serves as an excellent trigger for releasing drugs specifically within tumor cells. In this study, we designed an activatable circular antisense oligonucleotide (cASO) by incorporating a head-to-tail cyclization mediated by an NQO1-responsive trimethyl-locked quinone propionate (Q3PA), coupled with a self-immolative linker. The resulting circular structure prevented the cASO from binding to the target mRNA, thereby avoiding gene silencing. However, upon encountering NQO1, the circular form was converted to a linear form, leading to the silencing of the targeted gene. In vitro experiments demonstrated significant tumor-cell-specific activity of the cASO, while in vivo studies using an A549-Luc orthotopic lung tumor model revealed a substantial antitumor effect, primarily attributed to the suppression of survivin expression. This NQO1-activatable cASO represents a novel strategy for achieving tumor-cell-specific gene silencing and holds promise for the development of ASO prodrugs with enhanced therapeutic potentials.

In this paper, we discuss the evolution dynamics of Hermite-cos-Gauss (HcG) beams with initial isophase wavefront bending in optical media with nonlocal nonlinearity. Nonlocal nonlinearity can induce nonlinear refractive index potential wells, resulting in rich nonlinear physical transmission characteristics of optical beams. The initial phase wavefront bending means that the isophase surface of the HcG beam at the incident plane is not a plane and has a certain wavefront curvature. The results show that when the initial isophase wavefront of HcG beams is not a plane, they can only form breathing solitons, that is, its transverse statistical width changes periodically during propagation. A detailed analysis on the breathing period, breathing range, breathing velocity, breathing acceleration and other dynamic characteristics of HcG breathing solitons are given. The transverse energy distribution at different evolution distances and the evolution process of transverse energy flow of HcG breathing solitons are discussed. Some typical dynamic characteristics of HcG breathing solitons are demonstrated through numerical simulations.

Over the last 30 years, despite considerable research and endeavors aimed at harnessing aptamers as pharmaceutical molecules, the progress in developing aptamer-based drugs has been falling short of expectations. Sequential steps of affinity molecule acquisition and functional screening are typically required for discovering affinity-based macromolecule therapeutics, which can be time-consuming and limiting in candidate selection. Additionally, aptamers often necessitate tedious postselection modifications to overcome pharmacokinetic limitations, which usually impede the binding affinity. Herein, we propose a novel in vitro screening platform termed Functional Aptamers in vitro Evolution (FAIVE), which integrates affinity molecule acquisition with functional screening and introduces chemical diversity during the process. This platform aims to rapidly generate functional aptamers capable of binding to target proteins and regulating their functions. Illustrated by targeting intranuclear RNA-protein interactions involving HIV-1 Tat protein and TAR RNA, FAIVE demonstrates a selection of functional aptamers with significant intracellular blocking effects. The study also explores lipid nanoparticle delivery systems to enhance intracellular delivery efficiency, expanding aptamer targeting potential to broader intracellular and intranuclear domains. This study emphasizes the potential of FAIVE to expedite the development of aptamer-based drugs and facilitate the creation of more versatile and effective therapeutics.

The transmission characteristics of a quadrupole beam with a novel orbital angular momentum is investigated. The rotational mode transformation of this beam during transmission in strongly nonlocal nonlinear materials is analyzed and illustrated.

The evolution of a controllable vortex anomalous hollow beam (CVAHB) in free space is studied theoretically and numerically. Based on the Collins integral, the analytical formula of its propagation under free space paraxial approximation is derived. The corresponding beams with different parameters are simulated numerically, and the influence of each beam parameter on the beam type and intensity distribution during beam propagation is studied. Through the parameter control, the CVAHB can present a variety of intensity modes, such as hollow, three-segment, boat, etc. It is obvious that the evolution of CVAHB is different from that of the controllable anomalous hollow beam (CAHB). By changing the value of the topological charge (TC), the role of the orbital angular momentum (OAM) in the transverse distribution and propagation of light intensity is studied in detail.

The transmission characteristics of circular–linear edge dislocation vortex (CLEDV) beams in optical nonlocal medium is investigated analytically and numerically in detail. The analytical expression for the transmission of CLEDV beams is derived, and the transmission characteristics of CLEDV beams are illustrated in figures. The influence of various parameters of CLEDV beams on transmission characteristics is discussed, including statistical spot size, input power, topological charge, etc. The results indicate that the main transverse intensity of CLEDV beams can maintain a crescent shaped distribution and rotate periodically under the influence of topological charges. For different input powers, the variations of the statistical spot size of CLEDV beams in two transverse directions exhibit diverse behaviors: they can be diametrically opposite, simultaneously expand or compress, remain constant in one direction while periodically changing in the other. This complexity highlights the intricate dynamics of CLEDV beams in optical nonlocal medium.

Cancer immunotherapy has greatly improved the prognosis of tumor-bearing patients. Nevertheless, cancer patients exhibit low response rates to current immunotherapy drugs, such as PD1 and PDL1 antibodies. Cyclic dinucleotide analogs are a promising class of immunotherapeutic agents. In this study, in situ autologous tumor vaccines, composed of Bis-2′-F-cGSASMP phosphonothioate isomers (FGA-di-pS-2 or FGA-di-pS-4) and cytidinyl/cationic lipids (Mix), were constructed. Intravenous (i.v.) and intratumoral (i.t.) injection of FGA-di-pS-2/Mix or FGA-di-pS-4/Mix enhanced the immunogenic cell death of tumor cells in vivo, leading to the exposure and presentation of whole tumor antigens, inhibiting tumor growth in both LLC and EO771 tumor in situ murine models and increasing their survival rates to 50% and 23%, respectively. Furthermore, the tumor-bearing mice after treatment showed potent immune memory efficacy and exhibited 100% protection against tumor rchallenge. i.v. administration of FGA-di-pS-2/Mix potently promoted DC maturation, M1 macrophage polarization and CD8+ T-cell activation and decreased the proportion of Treg cells in the tumor microenvironment. Notably, two doses of ICD-debris (generated by FGA-di-pS-2 or 4/Mix-treated LLC cells) protected 100% of mice from tumor growth. These tumor vaccines showed promising results and may serve as personalized cancer vaccinations in the future.

In this paper, based on the nonlocal nonlinear Schrödinger equation, the nonlinear transmission characteristics of elliptical sine-Gaussian cross-phase (ESGCP) beams in strongly nonlocal nonlinear media are researched, and propagation expression of ESGCP beams in transmission process is given. One of the characteristics of beams is that the array mode and the hollow mode can be transformed into each other during the transmission process, which can produce more abundant light intensity modes. Numerical simulation is used to determine how the parameters in the initial propagation equation affect the beam width. In addition, evolution laws of light intensity, phase, and critical power are explored. The results show that the evolution of the beams is controlled by the parameters of the sine term and the cross-phase term in the initial propagation expression. The relationship between initial incident power and evolution period is introduced, and the reason is explained. The beams have great potential for development in the fields of optical communication and light capture.

The propagation dynamics of the complex variable cosine-Gaussian cross-phase (CVCGCP) array beams in strongly nonlocal nonlinear media are researched based on the nonlocal nonlinear Schrödinger equation. Under the effect of cross-phase, the transverse mode of CVCGCP array beams changes periodically and rotates during propagation. Compared with higher-order temporal solitons in nonlinear optical fibers, CVCGCP array beams can be considered as a new form of higher-order spatial solitons. The expression of the optical field distribution for the propagation evolution of CVCGCP array beams is presented. According to the different parameters, three cases are studied in detail. The light intensity pattern, phase and statistical width of CVCGCP array beams are discussed and analyzed. The results show that CVCGCP array beams have rich transmission characteristics and can form a linear shape distribution, which has the practical application value. By selecting the parameters, the light intensity patterns can be repeated and controlled, so as to achieve the purpose of controlling the light intensity patterns. The results of this paper enrich the types of higher-order spatial solitons, and also provide theoretical references for beam control and information transmission, etc.

Based on the nonlocal nonlinear Schrödinger equation, the propagation characteristics of transverse cross-modulated cosine-Gaussian (TCMCG) breathing solitons in strongly nonlocal media are studied. A series of mathematical expressions are provided to describe the propagation dynamics characteristics of the TCMCG breathing solitons, including the soliton width, soliton width change rate, soliton width extreme values, change rates of soliton width extreme values, phase wavefront curvature and phase wavefront curvature extreme values, etc. The research results indicate that by modulating TCMCG breathing solitons, generalized high-order spatial solitons can be formed with periodic changes in light intensity modes but unchanged in beam width. The cosine function parameter has a significant impact on the propagation dynamics characteristics, which appears in the initial expression and plays a cross modulation role in the transverse spatial light intensity. The effect of the initial incident power on soliton width extreme values and phase wavefront curvature extreme values is also discussed.

The propagation dynamics of lossy quadru-pole breather in strongly nonlocal nonlinear media are studied by variational method. The approximate evolution equation of several important parameters describing the transmission characteristics of quadrupole breather is obtained analytically. The characteristics of oscillating transmission are explained physically by analogy with classical mechanics. The numerical simulation is carried out to illustrate the accuracy of the analytical solution, and it is found that within a certain propagation distance, the degree of nonlocal is larger, and the degree of agreement between analytical and numerical solutions is higher. The evolution characteristics of beam width, wavefront curvature, and light intensity are analyzed by selecting appropriate nonlocal degrees, incident power, and loss coefficients. The media losses must be considered for the beam propagation in actual physical systems. Therefore, the absorption effect of light media on beam energy is considered, the attenuation characteristics of quadrupole beam intensity under different incident powers are obtained, and the soliton power with relatively high information transmission accuracy. Our theoretical analysis further improves and enriches the soliton theory, and will pave the way for the experimental observation of quadrupole solitons in nonlocal media.

Nucleic acid drugs are attracting significant attention as prospective therapeutics. However, their efficacy is hindered by challenges in penetrating cell membranes and reaching target tissues, limiting their applications. Nucleotidyl lipids, with their specific intermolecular interactions such as H-bonding and π-π stacking, offer a promising solution as gene delivery vehicles. In this study, a novel series of nucleotide-based amphiphiles were synthesized. These lipid molecules possess the ability to self-assemble into spherical vesicles of appropriate size and zeta potential in aqueous solution. Furthermore, their complexes with oligonucleotides demonstrated favorable biocompatibility and exhibited antiproliferative effects against a broad range of cancer cells. Additionally, when combined with the cationic lipid CLD, these complexes displayed promising in vitro performance and in vivo efficacy. By incorporating DSPE-PEGylated cRGD into the formulation, targeted accumulation of siG12D in pancreatic cancer cells increased from approximately 6% to 18%, leading to effective treatment outcomes (intravenous administration, 1 mg/kg). This finding holds significant importance for the liposomal delivery of nucleic acid drugs to extrahepatic tissues.