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The tumor entrance of drug delivery systems, including therapeutic proteins and nanomedicine, plays an essential role in affecting the treatment outcome. Nanoparticle size is a critical but contradictory factor in making a trade-off among blood circulation, tumor accumulation, and penetration. Here, this work designs a series of single-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) nanoprobes with well-defined sizes to precisely explore the size-dependent tumor entrance in vivo. The MRI nanoprobes obtained by divergent synthesis contain a core molecule of macrocyclic Gd(III)-chelate and different layers of dendritic lysine units, mimicking globular protein. This work finds that the r1 relaxivity and MR imaging signals increase with the nanoparticle size. The nanoprobe with a lower limit of critical size threshold ≈8.0 nm achieves superior tumor accumulation and penetration. These single-molecule MRI nanoprobes can be served to precisely examine the size-related nanoparticle-biological interactions.

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Extracellular vesicles (EVs), including microparticles and exosomes, have emerged as potential tools for tumor targeting delivery during the past years. Recently, mass of strategies are applied to assist EVs to accumulate and penetrate into deep tumor sites. In this review, EVs from different cells with unique innate characters and engineered approaches (e.g. chemical engineering, genetical engineering and biomimetic engineering) as drug delivery systems to enhance tumor accumulation and penetration are summarized. Meanwhile, efficient biological function modulation (e.g. extracellular matrix degradation, mechanical property regulation and transcytosis) is introduced to facilitate tumor accumulation and penetration of EVs. Finally, the prospects and challenges on further clinical applications of EVs are discussed.

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Liposomes are the first and mostly explored nanocarriers for cancer drug delivery, which have shown great promise in clinical applications, but their limited accumulation and penetration into the tumor interstitial space, significantly reduce the therapeutic efficacy. Here, a γ-glutamyltranspeptidase (GGT)-triggered charge-switchable approach is reported that can trigger the fast endocytosis and transcytosis of the liposome in tumor microenvironments to overcome the harsh biological barriers in tumor tissues. The active transporting liposomal nanocarrier (GCSDL) is prepared by surface modification with a glutathione (GSH) moiety and encapsulated with doxorubicin (DOX). When the GCSDL contacts with tumor vascular endothelial cells, the overexpressed GGT enzyme on cytomembrane catalyzes the hydrolysis of GSH to generate cationic primary amines. The cationic GCSDL triggers fast caveolae-mediated endocytosis and vesicle-mediated transcytosis, resulting in sequential transcytosis to augment its tumor accumulation and penetration. Along with continual intercellular transportation, GCSDL can release DOX throughout the tumor to induce cancer cell apoptosis, resulting in complete eradication of hepatocellular carcinoma and cessation of pancreatic ductal adenocarcinoma's progression. This study develops an efficient strategy to realize high tumor accumulation and deep penetration for the liposomal drug delivery system via active transcytosis.

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Reversing multidrug resistance (MDR) remains a big challenge in cancer therapy. Combining the hyperthermia and chemotherapy is a promising strategy for efficient cancer treatment with MDR reversal. Gold nanocages (GNCs) are an ideal photothermal (PTT)-chemotherapy integration platform due to their good photothermal conversion efficiency and the unique hollow interiors. However, insufficient tumor cell internalization and in vivo premature drug leakage restrict the anticancer activity of GNCs-based drug delivery systems. Methods: pH low insertion peptide (pHLIP)- and thermoresponsive poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate) polymer-conjugated GNCs were rationally constructed to load anticancer drug doxorubicin (DOX@pPGNCs). Tumor acidic environment-responsive tumor cell internalization, and near-infrared (NIR) laser-induced tumor accumulation, penetration and on-demand drug release were systematically examined. Results: DOX@pPGNCs display good photothermal efficacy and thermoresponsive property. NIR laser irradiations at the tumor site significantly enhance tumor accumulation and penetration. Once DOX@pPGNCs reach the tumor site, the conformational transformation of pHLIP at the acidic tumor microenvironment contributes to the enhanced cellular internalization. Furthermore, NIR laser-triggered photothermal effects induce the shrinkage of thermoresponsive polymer, resulting in the opening of the pores of GNCs and a rapid intracellular DOX release to the nuclei. DOX@pPGNCs exhibit synergistic antitumor effect with MDR reversal in vitro and in vivo. Conclusion: DOX@pPGNCs present strong potential to overcome MDR in cancer.

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Ideal anticancer nano drug delivery systems (NDDSs) need to overcome a series of physiological barriers including blood circulation, tumor accumulation, tumor penetration, internalization by cancer cells, lysosomal escape, and on-demand intracellular drug release following systemic administration. However, it remains a big challenge to construct NDDSs that can overcome all the barriers at the same time. Here, we develop zwitterionic temperature/redox-sensitive nanogels loaded with near-infrared (NIR) dye Indocyanine green (ICG) and anticancer drug doxorubicin (I/D@NG). I/D@NG exhibits enhanced photothermal effects, and NIR irradiation markedly decreases its diameter. NIR irradiation at tumor sites significantly enhances tumor accumulation, tumor penetration, and cellular uptake of I/D@NG with prolonged blood circulation time. Furthermore, I/D@NG can effectively escape from lysosomes by singlet oxygen-induced lysosomal disruption, and DOX is then sufficiently released from the nanogels to the nucleus in response to high intracellular GSH and photothermal effects. This nanoplatform for thermo-chemotherapy not only efficiently exerts synergistic cytotoxicity but also overcomes all the physiological barriers of therapeutic agent, thereby providing a substantial in vivo anticancer effect. The multiple functions of I/D@NG provide new insights into designing nanoplatforms for synergistic cancer therapy.

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Efficient accumulation and intracellular drug release in cancer cells remain a crucial challenge in developing ideal anticancer drug delivery systems. Here, poly(N-isopropylacrylamide)-ss-acrylic acid (P(NIPAM-ss-AA)) nanogels based on NIPAM and AA cross-linked by N,N'-bis(acryloyl)cystamine (BAC) were constructed by precipitation polymerization. The nanogels exhibited pH/redox dual responsive doxorubicin (DOX) release behavior in vitro and in tumor cells, in which DOX release from nanogels was accelerated in lysosomal pH (pH 4.5) and cytosolic reduction (10 mM GSH) conditions. Moreover, intracellular tracking of DOX-loaded nanogels confirmed that after the nanogels and the loaded DOX entered the cells simultaneously mainly via lipid raft/caveolae-mediated endocytosis, DOX-loaded nanogels were transported to lysosomes and then the loaded DOX was released to nucleus triggered by lysosomal pH and cytoplasmic high GSH. MTT analysis showed that DOX-loaded nanogels could efficiently inhibit the proliferation of HepG2 cells. In vivo animal studies demonstrated that DOX-loaded nanogels were accumulated and penetrated in tumor tissues more efficiently than free DOX. Meanwhile, DOX-loaded nanogels exhibited stronger tumor inhibition activity and fewer side effects. This study indicated that pH/redox dual-responsive nanogels might present a prospective platform for intracellular drug controlled release in cancer therapy.

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Small-interfering RNA (siRNA) is both a powerful tool in research and a promising therapeutic platform to modulate expression of disease-related genes. Malignant tumors are attractive disease targets for nucleic acid-based therapies. siRNA directed against oncogenes, and genes driving metastases or angiogenesis have been evaluated in animal models and in some cases, in humans. The outcomes of these studies indicate that drug delivery is a significant limiting factor. This review provides perspectives on in vivo validated nanoparticle-based siRNA delivery systems. Results of recent advances in liposomes and polymeric and inorganic formulations illustrate the need for mutually optimized attributes for performance in systemic circulation, tumor interstitial space, plasma membrane, and endosomes. Physiochemical properties conducive to efficient siRNA delivery are summarized and directions for future research are discussed.