Liangliang Chen,Siyuan Chen,Zhanbo Yi,Xianjiang Wu,Shuwen Zhong,Leiqiang Mao,Zesheng Wang,Qi Shuai,Xin Li
Cationic polymers like polyethyleneimine (PEI) are widely used for siRNA delivery, but their high positive charge density often compromises biocompatibility and in vivo stability. Balancing effective siRNA binding with reduced cytotoxicity remains a critical challenge for clinical translation. Here, we report a dual-functional modification strategy for PEI using oligosaccharides (maltose/maltotriose) and hydrophobic n-octanal to mitigate excessive cationic charge, enhance stability, and improve delivery efficiency. By synthesizing oligosaccharide-modified PEIs (OM-PEIs) and hydrophobically modified OM-PEIs (H-OM-PEIs), we identified PEI 25k -based derivatives (HC4 and HD4) as top performers, achieving complete siRNA loading at a low polymer:siRNA mass ratio (4:1, wt/wt) while exhibiting 50 % reduced protein adsorption and superior siRNA protection compared to unmodified PEI 25k . The hydrophobic modification enabled H-OM-PEIs to form compact nanoparticles with enhanced cellular uptake, leading to robust luciferase silencing in HeLa cells (2.5-fold improvement over PEI 25k ). Notably, in vivo studies revealed significant liver accumulation alongside detectable tumor delivery. This study demonstrated that combining oligosaccharide and alkyl modifications of PEI can reduce surface charge and protein adsorption while maintain high siRNA delivery efficiency, thereby mitigating the inherent toxicity of PEI and enhancing nanoparticle stability, which contributes to the advancement of PEI-based delivery systems in practical applications.
Lysosomal entrapment and liver accumulation are the two main obstacles faced by many anticancer drugs for achieving satisfactory therapeutic outcomes. Here, we develop a facile one-step hydrothermal synthetic route to prepare trace metal (M)-, N-, and O-doped carbon-dominated nanoparticles (termed as MNOCNPs, M = Ni, Pd, or Cu, metal content: <0.1 mol%) with exceptional photothermal properties (e.g., the ultrahigh extinction coefficient of 32.7 L g −1 cm −1 ), which can simultaneously realize preferable endoplasmic reticulum (ER) targeting and specific tumor enrichment without noticeable liver accumulation after poly(ethylene glycol) (PEG) conjugation. More interestingly, the PEG-modified MNOCNPs with nanoscale lengths exhibit considerable nucleolar delivery and increased tumor accumulation upon laser irradiation. After fluorescence labeling, these PEG-modified MNOCNPs are suitable for fluorescence/photoacoustic/thermal triple-modal imaging-guided photothermal cancer treatment. Additionally, the ultralow metal content ensures the exceptional biosafety of the nanoagents. The present work provides a novel, facile, and general synthetic method of carbon-dominated nanoparticles with superior photothermal properties for highly efficient tumor ablation, and the large-organelle (ER and nucleus)-targeted cancer therapeutic strategy may represent an alternative solution for optimizing the anticancer efficacy of nanomaterials . Statement of Significance Limited wire-like nanomaterials have been used for biomedical applications due to their lack of intrinsic photothermal properties, poor cellular uptake and tumor accumulation, and potential biotoxicity arising from their micrometer lengths and/or massive heavy metal doping. Besides, the clinical applications of many nanoagents are hindered by their tendency to accumulate in liver, which may cause severe liver toxicity. Herein, we develop for the first time a one-step hydrothermal method to prepare wire-like trace metal-, N-, and O-doped carbon-dominated nanoparticles with excellent photothermal properties, massive cellular uptake, preferable ER localization, selective tumor targeting with negligible liver deposition, laser irradiation-enhanced nucleolar delivery and tumor accumulation, and multimodal imaging-guided cancer therapy. This work opens a new window for simultaneously overcoming lysosomal entrapment and liver accumulation in cancer therapy.
危险品化学品经营许可证（带存储）