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The combination of two or more drugs with different mechanisms of action is a promising strategy for circumventing multidrug resistance (MDR). However, the antitumor effect of nanosystems is usually limited due to the simultaneous release of different payloads at a single location rather than at their respective sites of action. Herein, we report a GSH and pH dual responsive nanoplatform encapsulated with doxorubicin (DOX) and resiquimod (R848) (GPNP) for combinatorial chemotherapy against cancer cells with drug resistance. GPNP possesses a core-shell structure wherein the polymer shell detaches in the acidic and sialic acid (SA)-rich environment. This leads to the release of R848 into the tumor microenvironment (TME), thereby reprogramming M2 macrophages into M1 macrophages and exposing the core CS(DOX)-PBA to kill MCF-7/ADR cells. Additionally, the nitric oxide (NO) generated by M1 macrophages can suppress the P-glycoprotein (P-gp) expression to reduce the efflux of chemotherapy drugs, thus playing a combined role in overcoming MDR. In vitro studies have demonstrated the effectiveness of GPNP in reprogramming M2 macrophages and inducing apoptosis in MCF-7/ADR cells, resulting in enhanced antitumor efficacy. This work proposed an effective combination strategy to combat chemoresistance, providing new insights into the development of innovative combinatorial therapies against MDR tumors.

Lipid-based nanoparticles have made a breakthrough in clinical disease as delivery systems due to their biocompatibility, thermal and long-term stability, high loading ability, simplicity of preparation, inexpensive production costs, and scalable manufacturing production. In particular, during the COVID-19 pandemic, this delivery system served as a vital vaccine component for virus confrontation. To obtain effective drug delivery, lipid-based nanoparticles should reach the desired sites with high efficiency, enter target cells, and release drugs. The structures and compositions of lipid-based nanoparticles can be modified to regulate these behaviors in vivo to enhance the therapeutic effects. Herein, we briefly review the development of lipid-based nanoparticles, from simple self-assembled nanovesicle-structured liposomes to multifunctional lipid nanoparticles. Subsequently, we summarize the strategies that regulate their tissue distribution, cell internalization, and drug release, highlighting the importance of the structural and componential design. We conclude with insights for further research to advance lipid-based nanotechnology.

Drug delivery systems (DDS) are extensively studied to improve the solubility, stability, pharmacokinetic, and biodistribution of chemotherapeutics. However, the drug delivery efficiency of traditional DDS is often limited by the complicated biological barriers in vivo. Herein, a multistage adaptive nanoparticle (MAN) that simultaneously overcomes multiple biological barriers to achieve tumor-targeted drug delivery with high efficiency is presented. MAN has a core-shell structure, in which both the core and the shell are made of responsive polymers. This structure allows MAN to present different surface properties to adapt to its surrounding biological microenvironment, thereby achieving enhanced stability in blood circulation, improved tumor accumulation and cellular internalization in tumor tissues, and effective release of drug in cells. With these unique characteristics, the MAN loaded with docetaxel achieves effective tumor suppression with reduced systemic toxicity. Furthermore, MAN can load almost any hydrophobic drugs, providing a general strategy for the tumor-targeted delivery of hydrophobic drugs to overcome the multiple biological barriers and improve the efficacy of chemotherapy., (© 2021 Wiley-VCH GmbH.)

Although adoptive transfer of therapeutic cells to cancer patients is demonstrated with great success and fortunately approved for the treatment of leukemia and B-cell lymphoma, potential issues, including the unclear mechanism, complicated procedures, unfavorable therapeutic efficacy for solid tumors, and side effects, still hinder its extensive applications. The explosion of nanotechnology recently has led to advanced development of novel strategies to address these challenges, facilitating the design of nano-therapeutics to improve adoptive cell therapy (ACT) for cancer treatment. In this review, the emerging nano-enabled approaches, that design multiscale artificial antigen-presenting cells for cell proliferation and stimulation in vitro, promote the transducing efficiency of tumor-targeting domains, engineer therapeutic cells for in vivo imaging, tumor infiltration, and in vivo functional sustainability, as well as generate tumoricidal T cells in vivo, are summarized. Meanwhile, the current challenges and future perspectives of the nanostrategy-based ACT for cancer treatment are also discussed in the end., (© 2021 Wiley-VCH GmbH.)

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) enzyme, Cas13a, holds great promise in cancer treatment due to its potential for selective destruction of tumor cells via collateral effects after target recognition. However, these collateral effects do not specifically target tumor cells and may cause safety issues when administered systemically. Herein, a dual-locking nanoparticle (DLNP) that can restrict CRISPR/Cas13a activation to tumor tissues is described. DLNP has a core-shell structure, in which the CRISPR/Cas13a system (plasmid DNA, pDNA) is encapsulated inside the core with a dual-responsive polymer layer. This polymer layer endows the DLNP with enhanced stability during blood circulation or in normal tissues and facilitates cellular internalization of the CRISPR/Cas13a system and activation of gene editing upon entry into tumor tissue. After carefully screening and optimizing the CRISPR RNA (crRNA) sequence that targets programmed death-ligand 1 (PD-L1), DLNP demonstrates the effective activation of T-cell-mediated antitumor immunity and the reshaping of immunosuppressive tumor microenvironment (TME) in B16F10-bearing mice, resulting in significantly enhanced antitumor effect and improved survival rate. Further development by replacing the specific crRNA of target genes can potentially make DLNP a universal platform for the rapid development of safe and efficient cancer immunotherapies., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Current cancer immunotherapies including chimeric antigen receptor (CAR)-based therapies and checkpoint immune inhibitors have demonstrated significant clinical success, but always suffer from immunotoxicity and autoimmune disease. Recently, nanomaterial-based immunotherapies are developed to precisely control in vivo immune activation in tumor tissues for reducing immune-related adverse events. However, little consideration has been put on the spatial modulation of interactions between immune cells and cancer cells to optimize the efficacy of cancer immunotherapies. Herein, a rational design of immunomodulating nanoparticles is demonstrated that can in situ modify the tumor cell surface with natural killer cell (NK cell)-activating signals to achieve in situ activation of tumor-infiltrating NK cells, as well as direction of their antitumor immunity toward tumor cells. Using these immunomodulating nanoparticles, the remarkable inhibition of tumor growth is observed in mice without noticeable side effects. This study provides an accurate immunomodulation strategy that achieves safe and effective antitumor immunity through in situ NK cell activation in tumors. Further development by constructing interactions with various immune cells can potentially make this nanotechnology become a general platform for the design of advanced immunotherapies for cancer treatments., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Because of their abnormal vasculature and the dense tumor extra-cellular matrix, solid tumors prevent the deep and uniform penetration of nanocarriers. Numerous studies have shown that nanocarriers with a positively charged surface exhibit enhanced tumor penetration. Therefore, a hypoxia responsive nanocarrier [responsive micelles (RMs)] was developed, which can gradually increase the positive surface charge by responding to hypoxia gradients, and eventually achieve deep penetration in tumors. The nanocarrier was composed of a poly(caprolactone) core and a mixed shell of poly(ethylene glycol) (PEG) and 4-nitrobenzyl chloroformate (NBCF)-modified polylysine (PLL). During the blood circulation, the NBCF-modified PLL was shielded by the PEG, which gave it the ability to inhibit its rapid removal by the immune system. After reaching the tumor, the hypoxia microenvironment triggered partial NBCF degradation that recovered the amine groups of PLL, leading to a remarkable change in the surface to a positively charged one that enabled the penetration of the nanocarrier into the tumor. As the nanocarrier penetrated into the interior of the tumor, the decrease in oxygen concentration led to the further degradation of the NBCF-modified PLL, resulting in the increase of the positive surface charge which further facilitated the deep penetration. The subsequent in vitro and in vivo experiments certified that RM/doxorubicin had a better penetration ability and improved inhibition efficacy on tumor tissues, which demonstrated its potential application in cancer therapy.

[Display omitted] • IMNP precisely delivers bindarit and alendronate to their sites of action. • IMNP's spatial control of drug release promotes the synergistic effect of drugs. • IMNP effectively depletes tumor-associated macrophages. • IMNP improves the therapeutic effects of anti-PD-1 therapy. Targeting the tumor-associated macrophages (TAMs) with combinational drugs is a promising strategy to improve immune checkpoint blocking therapies. To optimize the synergetic effect of TAM-depletion, it is required for the delivery system to deliver multiple therapeutic drugs to their corresponding action-sites. Herein, we design an immune modulating nanoparticle (IMNP) that can achieve a spatial control of the release sites of the drugs to synergistically deplete TAMs. IMNP has a core–shell structure in which the shell disassembles in acidic tumor microenvironment, resulting in the release of bindarit into the intercellular space to inhibit the recruitment of monocytes and exposing the core nCS(ALN)-Man to trigger the apoptosis of TAMs. With this unique feature, systemic administration of IMNP to tumor-bearing mice effectively eliminated TAMs and altered the immunosuppressing tumor environment, which significantly improved the anti-tumor efficacy of anti-PD-1. Considering the antitumor efficacy of chemotherapy, irradiation and vascular-targeted therapies is also counteracted by TAMs, IMNP could be further developed in combination with these therapies for cancer treatment, implying the potential as a general application to improve the efficacy of cancer therapies. [ABSTRACT FROM AUTHOR]