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The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANP MTO /ALCD) and a deformable nanoadjuvant (PPE R848 ). The ANP MTO /ALCD composite consisted of β-cyclodextrin-decorated alginate (Alg- g -CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANP MTO ) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPE R848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.

Purpose: Hepatitis B virus (HBV) infection is such a global health problem that hundreds of millions of people are HBV carriers. Current anti-viral agents can inhibit HBV replication, but can hardly eradicate HBV. Cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODNs) are an adjuvant that can activate plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) to induce therapeutic immunity for HBV eradication. However, efficient delivery of CpG ODNs into pDCs and cDCs remains a challenge. In this study, we constructed a series of cationic lipid-assisted nanoparticles (CLANs) using different cationic lipids to screen an optimal nanoparticle for delivering CpG ODNs into pDCs and cDCs., Methods: We constructed different CLAN CpG using six cationic lipids and analyzed the cellular uptake of different CLAN CpG by pDCs and cDCs in vitro and in vivo, and further analyzed the efficiency of different CLAN CpG for activating pDCs and cDCs in both wild type mice and HBV-carrier mice., Results: We found that CLAN fabricated with 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP) showed the highest efficiency for delivering CpG ODNs into pDCs and cDCs, resulting in strong therapeutic immunity in HBV-carrier mice. By using CLAN CpG as an immune adjuvant in combination with the injection of recombinant hepatitis B surface antigen (rHBsAg), HBV was successfully eradicated and the chronic liver inflammation in HBV-carrier mice was reduced., Conclusion: We screened an optimized CLAN fabricated with DOTAP for efficient delivery of CpG ODNs to pDCs and cDCs, which can act as a therapeutic vaccine adjuvant for treating HBV infection., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abnormal immune cell functions are commonly related to various diseases, including cancer, autoimmune diseases, and infectious diseases. Messenger RNA (mRNA)-based therapy can regulate the functions of immune cells or assign new functions to immune cells, thereby generating therapeutic immune responses to treat these diseases. However, mRNA is unstable in physiological environments and can hardly enter the cytoplasm of target cells; thus, effective mRNA delivery systems are critical for developing mRNA therapy. The two mRNA vaccines of Pfizer-BioNTech and Moderna have demonstrated that lipid nanoparticles (LNPs) can deliver mRNA into dendritic cells (DCs) to induce immunization against severe acute respiratory syndrome coronavirus 2, which opened the floodgates to the development of mRNA therapy. Apart from DCs, other immune cells are promising targets for mRNA therapy. This review summarized the barriers to mRNA delivery and advances in mRNA delivery for regulating the functions of different immune cells., (Copyright © 2021. Published by Elsevier B.V.)

Lymph nodes (LNs) are normally the primary site of tumor metastasis, and effective delivery of chemotherapeutics into LNs through systemic administration is critical for metastatic cancer treatment. Here, we uncovered that improved perfusion in a primary tumor facilitates nanoparticle translocation to LNs for inhibiting tumor metastasis. On the basis of our finding that an iCluster platform, which undergoes size reduction from ∼100 nm to ∼5 nm at the tumor site, markedly improved particle perfusion in the interstitium of the primary tumor, we further revealed in the current study that such tumor-specific size transition promoted particle intravasation into tumor lymphatics and migration into LNs. Quantitative analysis indicated that the drug deposition in LNs after iCluster treatment was significantly higher in the presence of a primary tumor in comparison with that after primary tumor resection. Early intervention of metastatic 4T1 tumors with iCluster chemotherapy and subsequent surgical resection of the primary tumor resulted in significantly extending animal survival, with 4 out of the 10 mice remaining completely tumor-free for 110 days. Additionally, in the more clinical relevant late metastatic model, iCluster inhibited the metastatic colonies to the lungs and extended animal survival time. This finding provides insights into the design of more effective nanomedicines for treating metastatic cancer.

Polymeric nanoparticles as drug delivery systems have the potential to improve the therapeutic efficacy and reduce the toxicity of chemotherapeutic drugs by enhancing the drug selectivity in vivo. The efficacy is directly dependent on the polymeric nanoparticles' in vivo fate. Therefore, it is very important to develop a method to stably label the polymeric nanoparticles for detecting the in vivo fate. Here, we report a method to stably label self-assembled nanoparticles by the incorporation of rhodamine B-conjugated poly(ε-caprolactone) (PCL-RhoB). Only 1% of PCL-RhoB was released from the RhoB-labeled polymeric nanoparticles (RhoB-PNPs) in phosphate buffer within 12 hours, which suggested that the signal of PCL-RhoB can be used to represent the behaviors of polymeric nanoparticles both in vitro and in vivo. PCL-RhoB could be effectively extracted and quantitatively detected by ultra-high-performance liquid chromatography (UPLC) in various media, such as PBS, a cell culture medium containing 10% FBS (pH = 7.4 and pH = 6.8), mouse serum, simulated intestinal fluid and cell or tissue lysis. The intracellular contents of PCL-RhoB in MDA-MB-231 cells detected by UPLC were linearly correlated to the concentration of the RhoB-PNPs. In addition, the contents of PCL-RhoB in plasma and the spleen were proportional to the injected dose of RhoB-PNPs in vivo. As an application example, the pharmacokinetics and biodistribution of the nanoparticles over time in vivo were analyzed following intravenous injection to confirm the feasibility of this method.

Engineering nanoparticles of reasonable surface poly(ethylene glycol) (PEG) length is important for designing efficient drug delivery systems. Eliminating the disturbance by other nanoproperties, such as size, PEG density, etc., is crucial for systemically investigating the impact of surface PEG length on the biological behavior of nanoparticles. In the present study, nanoparticles with different surface PEG length but similar other nanoproperties were prepared by using poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) copolymers of different molecular weights and incorporating different contents of PCL 3500 homopolymer. The molecular weight of PEG block in PEG-PCL was between 3400 and 8000 Da, the sizes of nanoparticles were around 100 nm, the terminal PEG density was controlled at 0.4 PEG/nm 2 (or the frontal PEG density was controlled at 0.16 PEG/nm 2 ). Using these nanoproperties well-designed nanoparticles, we demonstrated PEG length-dependent changes in the biological behaviors of nanoparticles and exhibited nonmonotonic improvements as the PEG molecular weight increased from 3400 to 8000 Da. Moreover, under the experimental conditions, we found nanoparticles with a surface PEG length of 13.8 nm (MW = 5000 Da) significantly decreased the absorption with serum protein and interaction with macrophages, which led to prolonged blood circulation time, enhanced tumor accumulation and improved antitumor efficacy. The present study will help to establish a relatively precise relationship between surface PEG length and the in vivo behavior of nanoparticles., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo. More importantly, after further encoding a guide RNA targeting Ntn1 (sgNtn1) into the plasmid, the resultant CLAN pM330/sgNtn1 successfully disrupted the Ntn1 gene in macrophages and their precursor monocytes in vivo, which reduced expression of netrin-1 (encoded by Ntn1) and subsequently improved type 2 diabetes (T2D) symptoms. Meanwhile, the Ntn1 gene was not disrupted in other cells due to specific expression of Cas9 by the CD68 promoter. This strategy provides alternative avenues for specific in vivo gene editing with the CRISPR/Cas9 system.

Surface charge plays an important role in determining the interactions of nanoparticles with biological components. Substantial studies have demonstrated that surface charge affects the fate of nanoparticles after intravenous administration; however, few studies have investigated the effect of surface charge on the bioavailability and absorption of nanoparticles after oral administration. In this study, polymeric nanoparticles with a similar particle size and surface polyethylene glycol (PEG) density, but with varying surface charges (positive, negative and neutral), were developed to study the effect of surface charge on the oral absorption of polymeric nanoparticles. The nanoparticles were constructed from polyethylene glycol-block-polylactic acid (PEG-PLA) with the incorporation of lipid components with different charges. Our results suggested that the positive surface charge facilitated the cellular uptake and transport of nanoparticles through both Caco-2 cells in vitro and small intestinal epithelial cells in vivo. The positively charged nanoparticles showed a favorable distribution in the small intestine, and significantly improved the oral bioavailability. This study presents valuable information towards the design of nanoparticles for improved oral drug delivery.

Nanocarriers with tumor-acidity-activated charge-conversional ability are of particular interest for targeted drug delivery in the field of precision nanomedicine. Nevertheless, the key challenge of this strategy is the slowness of reversing the surface charge at the tumor tissue. As a proof-of-concept, we synthesized the amphiphilic triblock polymer poly(ethylene glycol)-block-poly(2-carboxyethylacrylate)-block-poly(2-azepaneethylmethacrylate) (PEG-b-PCEA-b-PAEMA) to prepare the cisplatin-loaded nanocarrier UCC-NP/Pt. The PAEMA block at the physiological pH values was hydrophobic, which formed the core of UCC-NP/Pt. In contrast, at the tumor acidity, the tertiary amine groups of PAEMA block rapidly protonated, resulting in the ultrafast charge conversion of UCC-NP/Pt within 10 s. Such ultrafast charge-conversional effect more efficiently enhanced tumor cell internalization of nanocarriers, thus achieving targeted drug delivery, which in turn exhibited superior anticancer efficacy even in the cisplatin-resistant cells. This approach provides new avenues for tumor-acidity-activated targeted drug delivery.

The currently low delivery efficiency and limited tumor penetration of nanoparticles remain two major challenges of cancer nanomedicine. Here, we report a class of pH-responsive nanoparticle superstructures with ultrasensitive size switching in the acidic tumor microenvironment for improved tumor penetration and effective in vivo drug delivery. The superstructures were constructed from amphiphilic polymer directed assembly of platinum-prodrug conjugated polyamidoamine (PAMAM) dendrimers, in which the amphiphilic polymer contains ionizable tertiary amine groups for rapid pH-responsiveness. These superstructures had an initial size of ∼80 nm at neutral pH (e.g., in blood circulation), but once deposited in the slightly acidic tumor microenvironment (pH ∼6.5-7.0), they underwent a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units) and dissociated instantaneously into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature not only can facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention effect but also allows faster nanoparticle diffusion and more efficient tumor penetration. We have further carried out comparative studies of pH-sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition in both multicellular spheroids and poorly permeable BxPC-3 pancreatic tumor models, whose results demonstrate that the pH-triggered size switching is a viable strategy for improving drug penetration and therapeutic efficacy.

The core purpose of cancer immunotherapy is the sustained activation and expansion of the tumor specific T cells, especially tumor-infiltrating cytotoxic T lymphocytes (CTLs). Currently, one of the main foci of immunotherapy involving nano-sized carriers is on cancer vaccines and the role of professional antigen presenting cells, such as dendritic cells (DCs) and other phagocytic immune cells. Besides the idea that cancer vaccines promote T cell immune responses, targeting immune inhibitory pathways with nanoparticle delivered regulatory agents such as small interfering RNA (siRNA) to the difficultly-transfected tumor-infiltrating T cells may provide more information on the utility of nanoparticle-mediated cancer immunotherapy. In this study, we constructed nanoparticles to deliver cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)-siRNA (NPsiCTLA-4) and showed the ability of this siRNA delivery system to enter T cells both in vitro and in vivo. Furthermore, T cell activation and proliferation were enhanced after NPsiCTLA-4 treatment in vitro. The ability of direct regulation of T cells of this CTLA-4 delivery system was assessed in a mouse model bearing B16 melanoma. Our results demonstrated that this nanoparticle delivery system was able to deliver CTLA-4-siRNA into both CD4(+) and CD8(+) T cell subsets at tumor sites and significantly increased the percentage of anti-tumor CD8(+) T cells, while it decreased the ratio of inhibitory T regulatory cells (Tregs) among tumor infiltrating lymphocytes (TILs), resulting in augmented activation and anti-tumor immune responses of the tumor-infiltrating T cells. These data support the use of potent nanoparticle-based cancer immunotherapy for melanoma., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Poly(ethylene glycol) (PEG) is usually used to protect nanoparticles from rapid clearance in blood. The effects are highly dependent on the surface PEG density of nanoparticles. However, there lacks a detailed and informative study in PEG density and in vivo drug delivery due to the critical techniques to precisely control the surface PEG density when maintaining other nano-properties. Here, we regulated the polymeric nanoparticles' size and surface PEG density by incorporating poly(ε-caprolactone) (PCL) homopolymer into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) and adjusting the mass ratio of PCL to PEG-PCL during the nanoparticles preparation. We further developed a library of polymeric nanoparticles with different but controllable sizes and surface PEG densities by changing the molecular weight of the PCL block in PEG-PCL and tuning the molar ratio of repeating units of PCL (CL) to that of PEG (EG). We thus obtained a group of nanoparticles with variable surface PEG densities but with other nano-properties identical, and investigated the effects of surface PEG densities on the biological behaviors of nanoparticles in mice. We found that, high surface PEG density made the nanoparticles resistant to absorption of serum protein and uptake by macrophages, leading to a greater accumulation of nanoparticles in tumor tissue, which recuperated the defects of decreased internalization by tumor cells, resulting in superior antitumor efficacy when carrying docetaxel., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Polymeric nanoparticles have been widely used as nano-drug delivery systems in preclinical and clinical trials for cancer therapy, and these systems usually need to be sterically stabilized by poly(ethylene glycol) (PEG) to maintain stability and avoid rapid clearance by the immune system. Recently, zwitterionic materials have been demonstrated to be potential alternatives to the classic PEG. Herein, we developed two drug delivery systems stabilized by zwitterionic polyphosphoesters. These nanoparticles showed favourable stability and anti-protein absorption ability in vitro. Meanwhile, as drug carriers, these zwitterionic polyphosphoester-stabilized nanoparticles significantly prolonged drug circulation half-lives and increased drug accumulation in tumors, which was comparable to PEG-stabilized nanoparticles. Systemic delivery of doxorubicin (DOX) by zwitterionic polyphosphoester-stabilized nanoparticles significantly inhibited tumor growth in a MDA-MB-231 tumor model, suggesting the potential of zwitterionic polyphosphoester-based nanoparticles in anticancer drug delivery.

Basal-like triple negative breast cancer (TNBC) has received particular clinical interest due to its high frequency, poor baseline prognosis and lack of effective clinical therapy. Bortezomib, which was the first proteasome inhibitor approved for the treatment of multiple myeloma, has been proven to be worth investigating for this subtype of breast cancer. In our study, the amphiphilic copolymer poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) was utilized as an excellent delivery carrier of bortezomib (BTZ) to overcome its clinical limitations including low water solubility and unstable properties. Bortezomib encapsulated nanoparticles (NPBTZ) can efficiently deliver the drug into both CSCs (cancer stem cells) and non-CSCs, resulting in proliferation inhibition and apoptosis induction. Remarkably, NPBTZ can more effectively affect the stemness of CSCs compared with free BTZ. Administration of this drug delivery system can markedly prolong the bortezomib circulation half-life and augment the enrichment of drugs in tumor tissue, then enhance the suppression of tumor growth, suggesting the therapeutic promise of NPBTZ delivery in basal-like TNBC therapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aberrant DNA hypermethylation is critical in the regulation of renewal and maintenance of cancer stem cells (CSCs), which represent targets for carcinogenic initiation by chemical and environmental agents. The administration of decitabine (DAC), which is a DNA hypermethylation inhibitor, is an attractive approach to enhancing the chemotherapeutic response and overcoming drug resistance by CSCs. In this study, we investigated whether low-dose DAC encapsulated in nanoparticles could be used to sensitize bulk breast cancer cells and CSCs to chemotherapy. In vitro studies revealed that treatment with nanoparticles loaded with low-dose DAC (NPDAC) combined with nanoparticles loaded with doxorubicin (NPDOX) better reduced the proportion of CSCs with high aldehyde dehydrogenase activity (ALDH(hi)) in the mammospheres of MDA-MB-231 cells, and better overcame the drug resistance by ALDH(hi) cells. Subsequently, systemic delivery of NPDAC significantly down-regulated the expression of DNMT1 and DNMT3b in a MB-MDA-231 xenograft murine model and induced increased caspase-9 expression, which contributed to the increased sensitivity of the bulk cancer cells and CSCs to NPDOX treatment. Importantly, the combined treatment of NPDAC and NPDOX resulted in the lowest proportion of ALDH(hi) CSCs and the highest proportion of apoptotic tumor cells, and the best tumor suppressive effects in inhibiting breast cancer growth., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Synthetic lethal interaction provides a conceptual framework for the development of wiser cancer therapeutics. In this study, we exploited a therapeutic strategy based on the interaction between GATA binding protein 2 (GATA2) downregulation and the KRAS mutation status by delivering small interfering RNA targeting GATA2 (siGATA2) with cationic lipid-assisted polymeric nanoparticles for treatment of non-small-cell lung carcinoma (NSCLC) harboring oncogenic KRAS mutations. Nanoparticles carrying siGATA2 (NPsiGATA2) were effectively taken up by NSCLC cells and resulted in targeted gene suppression. NPsiGATA2 selectively inhibited cell proliferation and induced cell apoptosis in KRAS mutant NSCLC cells. However, this intervention was harmless to normal KRAS wild-type NSCLC cells and HL7702 hepatocytes, confirming the advantage of synthetic lethality-based therapy. Moreover, systemic delivery of NPsiGATA2 significantly inhibited tumor growth in the KRAS mutant A549 NSCLC xenograft murine model, suggesting the therapeutic promise of NPsiGATA2 delivery in KRAS mutant NSCLC therapy.

Two faced nanoparticles: A zwitterionic polymer-based nanoparticle with response to tumor acidity is developed for enhanced drug delivery to tumors. The nanoparticles are neutrally charged at physiological conditions and show prolonged circulation time; after leaking into tumor sites, in the acidic extracellular tumor environment (pH(e) ), nanoparticles are activated and become positively charged and are therefore efficiently taken up by tumor cells, leading to enhanced therapeutic effects in cancer treatment., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, we have designed a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system to overcome the challenges. The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (∼6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (∼5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.