Connective tissue growth factor (CTGF) is a key driver in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study presents a groundbreaking supramolecular cryo-shock bone marrow mononuclear cell system for targeted drug delivery in IPF. We incorporated antisense oligonucleotides (ASO) to inhibit CTGF and simultaneously encapsulated nintedanib using the ZMO-E5-NPs carrier for synergistic delivery. The cryo-shock treatment enhances cellular structural integrity and preserves receptor functionality, thereby extending cell viability. By modifying the E5 peptide and conjugating it with DSPE-PEG-MAL, we developed a composite carrier, ZMO-E5-NPs, which demonstrates efficient lung-targeting capability. This system enables rapid nanoparticle capture by fibroblasts through matrix metalloproteinase 2 (MMP2) recognition, ensuring precise delivery of both ASO and nintedanib. In a bleomycin-induced pulmonary fibrosis mouse model, ZMO-E5-NPs-ASO (nintedanib-containing group) significantly attenuated fibrosis progression, improved lung function, and exhibited excellent biocompatibility and safety, highlighting its potential as a novel therapeutic strategy for respiratory diseases.

Molecular glues (MGs), a class of small-molecule degraders, exhibit drug-like properties that generally conform to Lipinski's rule of five, while uniquely mediating the stabilization or induction of protein-protein interactions. By altering the surface properties of either target proteins or E3 ligases, MGs promote the formation of a ternary complex comprising the MG, an E3 ligase, and a target protein. This interaction facilitates the polyubiquitination and subsequent degradation of the target protein via the ubiquitin-proteasome system. Owing to its distinctive mechanism of action and broad therapeutic potential, MG is offering novel approaches to disease treatment. This review summarizes recent advances in MGs targeting NIMA-related kinase 7 (NEK7), WEE1, CDK2, GSPT1 and VAV1, emphasizing the rational design, benefits, and potential limitations, highlighting rational design principles, advantages, and current limitations including challenges in achieving selectivity and rational design that provide critical insights for enhancing MG efficacy. These developments are crucial for advancing the application and optimization of molecular glues targeting NEK7, WEE1, CDK2, GSPT1 and VAV1.

Nucleic acid-based therapies have emerged as promising strategies for the regulation of gene expression and the production of therapeutic antigens or proteins for a series of diseases, including cancers, rare diseases, and infectious diseases. However, their clinical application faces challenges. These include high molecular weight, limited cellular uptake, and susceptibility to enzymatic degradation by nucleases in vivo. Both viral and non-viral delivery vectors have been developed as a means of addressing these limitations, including lipid nanoparticles (LNPs), exosomes, polymers, and inorganic nanoparticles. Among these, LNPs have garnered significant attention due to their superior biocompatibility, high delivery efficiency and customizable design potential, as demonstrated by the clinical success of the FDA-approved siRNA drug Onpattro®. The critical role of nucleic acid drug carriers is discussed in this review. It also outlines the major types of carriers under development and examines the advancements and applications in LNP-based systems for nucleic acid delivery. By conducting a review of recent advancements in LNP design, delivery mechanisms, and clinical applications, this article aims to clarify the ways in which LNPs overcome delivery barriers, compare LNPs with other carriers, and identify key trends that can inform the development of next-generation LNP platforms for nucleic acid therapeutics.

Renal cell carcinoma (RCC) is a challenging urologic malignancy characterized by its aggressive nature, including invasion, metastasis, and treatment resistance. To explore multi-targeted therapies, we established an advanced clear cell renal cell carcinoma (ccRCC) model via orthotopic tumor transplantation in mice, and established another model simulating post-surgical recurrence by performing radical nephrectomy. We engineered a genetic circuit to reprogram the host liver as a bioreactor, enabling the production and delivery of in vivo self-assembled siRNAs (IVSA-siRNAs) for co-targeting VEGFR2 and mTOR. The efficacy and toxicity of this IVSA-siRNA system were evaluated and compared with the combination therapy of sunitinib and everolimus. In the established models, the combination therapy of sunitinib and everolimus showed efficacy but induced severe adverse effects. In contrast, IVSA-siRNAs potently silenced VEGFR2 and mTOR expression, achieving therapeutic effects in both advanced and radical nephrectomy ccRCC models without discernible toxicity.

Chemotherapeutic paclitaxel (PTX) formulations are widely used in clinical cancer treatment; however, they are also associated with concomitant programmed death-ligand (PD-L1) upregulation and an immunosuppressive microenvironment. Herein, we rationally designed carrier-free, reduction-sensitive PTX dimer self-assembling nanoprodrugs (diPC NPs), composed of a glutathione (GSH)-responsive PTX dimer prodrug (diPTX) and the PD-L1 downregulator celastrol (Cel) for combinational chemoimmunotherapy. Following intravenous administration, the diPC NPs exhibited prolonged blood circulation and preferential tumor accumulation by exploiting the enhanced permeability and retention effect. Subsequently, the elevated GSH levels in tumor cells cleaved the disulfide bonds, triggering the rapid release of PTX and Cel. The released PTX elicited potent cytotoxic effects and induced immunogenic cell death (ICD), whereas the released Cel synergistically enhanced ICD and downregulated PD-L1 expression in tumor cells. Together, these effects resulted in remarkable antitumor efficacy with exhibited a favorable safety profile within the therapeutic window in both Lewis lung carcinoma cells and B16F10 tumor-bearing mice. Our findings highlight a promising strategy for highly efficient combination chemoimmunotherapy.

Tumors pose a serious threat to human life and health. In recent years, gene therapy against tumors has garnered considerable attention. Small interfering RNAs (siRNAs), an important class of nucleic acid drugs, can silence the mRNAs of tumor-associated genes with high specificity through RNA interference (RNAi), inhibiting tumor-related signaling pathways or protein expression and thereby exerting anti-tumor effects. However, anti-tumor siRNA drugs are currently in the clinical research stage, and none of these drugs have been approved for marketing, mainly because of the challenges in terms of safety, efficacy and targeted delivery. Nano-delivery systems can enhance siRNA stability and improve siRNA pharmacokinetics and biodistribution, while increasing their uptake by target cells to achieve precise delivery and controlled release, thereby serving as a promising solution to overcome the challenges of siRNA drug application. This review summarizes the existing research on the nano-delivery systems currently available to help siRNAs achieve organ-targeted delivery and enhance the anti-tumor efficacy of siRNAs, discussing the characteristics of siRNA action and the unique advantages of different types of nano-delivery systems. The aim was to provide novel ideas for the design and optimization of siRNA-based drug delivery and the development of novel anti-tumor formulations to promote the clinical translation and application of siRNA drugs.

Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin (DOX) prodrug nanoparticles (CatB-NPs) for inducing tumor-specific immunogenic cell death (ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin B-activatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide (FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles (163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, CatB-NPs effectively induced cancer cell-specific ICD, while sparing normal cells and immune cells. When CatB-NPs-treated B16F10 cells were co-cultured with immune cells, CatB-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells (DCs). In melanoma models, CatB-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling high-dose treatment that induced robust ICD. Importantly, combination therapy with CatB-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, high-dose CatB-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.

Asthma, one of the most prevalent chronic inflammatory diseases, remains challenging to manage effectively. Current therapies commonly alleviate symptoms through broad immunosuppression and bronchodilation but fail to target disease-specific molecular pathways. Genetic intervention using small interfering RNA (siRNA) has emerged as a promising strategy for asthma therapy. However, its success is largely hindered by the lack of an efficient delivery approach targeting airway epithelial cells (AECs). Here, we developed a novel inhalable siRNA delivery system based on artificially prepared nanovesicles through designed extrusion processes of mesenchymal stem cells. To enable an effective inhalation delivery of siRNA via nanovesicles, various parameters, including extrusion cycles, membrane pore sizes, and centrifugal forces were examined through orthogonal testing. Results revealed that the artificially prepared nanovesicles demonstrated remarkable capability to deliver thymic stromal lymphopoietin-targeted siRNA into AECs and substantially suppressed the inflammatory pathways and goblet cell hyperplasia, and eventually achieved a significant inhibition of asthma symptoms in ovalbumin-induced asthma models. Thus, the present study provides a novel nebulized nanovesicle-based carrier for effective delivery of siRNA through local inhalation, offering a promising therapeutic delivery platform for asthma and potentially other respiratory diseases.

To enhance the anesthetic efficacy of propofol while mitigating its systemic toxicity and irreversible developmental neurotoxicity, we developed a strategy leveraging the neuroprotective effects of baicalin in combination with propofol anesthesia via baicalin-based nanocomposites. High propofol-loaded porous Baicalin-Fe(III) infinite coordination polymer@propofol nanocomposites were synthesized, wherein baicalin coordinates with Fe3+ ions to form porous nanoparticles that encapsulate propofol within a core-shell structure. These nanocomposites exhibited an average diameter of 92.3 ± 10.2 nm and a pore volume of 0.322 cm3/g, achieving ultra-high propofol loading (∼62%) with no detectable leakage over 100 d, attributed to their large surface area and strong molecular interactions. When combined with focused ultrasound (FUS) and microbubbles, the effective dose (ED50) of propofol decreased from 10 to 4.3 mg/kg, doubling the duration of anesthesia and extending the therapeutic window by 200%. Importantly, the therapeutic index improved 1.66-fold while vital physiological parameters remained stable. Histological analyses revealed an 80% reduction in neuronal injury compared to free propofol, and behavioral tests demonstrated significant enhancements in motor and cognitive performance, alongside recovery from propofol-induced irreversible developmental neurotoxicity, indicating effective neuroprotection. Collectively, this baicalin-propofol nanocomposite, coupled with FUS-mediated delivery, represents a promising approach for safe and long-term anesthesia in clinical applications.