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Antimicrobial peptides (AMPs) hold great potential for use in tumor treatment. However, developing AMP-based antitumor therapies is challenging due to circulatory instability, hemolytic toxicity, low selectivity, and poor cell permeability of AMPs. In this study, a polymeric carrier for AMPs (denoted as PAMP m -co-PPBE n /PCA) is presented that effectively enhances their anticancer efficacy while minimizing their potential side effects. By integrating multiple responsive structures at the molecular level, the carrier finely controls the spatial distribution of AMPs in different biological microenvironments, thereby effectively modulating their membranolytic ability. Upon employing KLA as the model AMP, the polymeric carrier's hemolytic toxicity during blood circulation is suppressed, its cellular internalization when reaching tumor tissues facilitated, and its membranolytic toxicity toward the mitochondria upon entering cancer cells restored and further enhanced. Animal studies indicate that this approach significantly improves the antitumor efficacy of KLA and reduces its toxicity. Considering that the loading method for most AMPs is identical to that of KLA, the polymeric carrier reported in this study may provide a feasible approach for the development of AMP-based cancer treatments., (© 2022 Wiley-VCH GmbH.)

Antibodies have shown potential to deplete immunosuppressive factors in tumor tissues. However, intrinsic drawbacks, including time-consuming processes in preparation, high cost, and short half-life time, greatly restrict their applications. In this work, we report an antibody-like polymeric nanoparticle (APN) that is capable of specifically capturing and removing galectin-1 in tumor tissues, thereby enhancing the antitumor T-cell responses. The APN is composed of an albumin-polymer hybrid nanoparticle (core) and an acid-responsive PEG shell. The core of the APN contains multiple recognition units and Tuftsin peptides to capture target factors and activate macrophage-mediated phagocytosis, respectively. By employing galactose as recognition units, the APN facilitated the phagocytosis of galectin-1 in tumor tissues, thereby improving the antitumor responses of tumor-infiltrating T cells. Since the recognition units in the APN can be further replaced to capture and remove other peptides/proteins, the APN provides a feasible approach for the development of synthetic nanoformulations to regulate biological systems and treat diseases.

Combination therapy based on molecular drugs and therapeutic genes provides an effective strategy for malignant tumor treatment. However, effective gene and drug combinations for cancer treatment are limited by the widespread antagonism between therapeutic genes and molecular drugs. Herein, a calixarene-embedded nanoparticle (CENP) is developed to co-deliver molecular drugs and therapeutic genes without compromising their biological functions, thereby achieving interference-free gene-drug combination cancer therapy. CENP is composed of a cationic polyplex core and an acid-responsive polymer shell, allowing CENP loading and delivering therapeutic genes with improved circulation stability and enhanced tumor accumulation. Moreover, the introduction of carboxylated azocalix[4]arene, which is a hypoxia-responsive calixarene derivatives, in the polyplex core endows CENP with the capability to load molecular drugs through the host-guest complexation as well as inhibit the interference between the drugs and genes by encapsulating the drugs into its cavity. By loading doxorubicin and a plasmid DNA-based CRISPR interference system that targets miR-21, CENP exhibits the significantly enhanced anti-tumor effects in mice. Considering the wide variety of calixarene derivatives, CENP can be adapted to deliver almost any combination of drugs and genes, providing the potential as a universal platform for the development of interference-free gene-drug combination cancer therapy., (© 2021 Wiley-VCH GmbH.)

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9) system holds great promise for the cancer gene therapy. However, due to complicated signal networks and various compensatory mechanisms in tumors, adjusting a single molecular pathway has limited effects on cancer treatments. Herein, a virus-like nanoparticle (VLN) was reported as a versatile nanoplatform to co-deliver CRISPR/Cas9 system and small molecule drugs for effective malignant cancer treatment. VLN has a core-shell structure, in which small molecule drugs and CRISPR/Cas9 system are loaded in the mesoporous silica nanoparticle (MSN)-based core, which is further encapsulated with a lipid shell. This structure allows VLN maintaining stable during blood circulation. As reaching tumors, VLN releases the CRISPR/Cas9 system and small molecule drugs in response to the reductive microenvironment, resulting in the synergistic regulation of multiple cancer-associated pathways. By loading a single guide RNA (sgRNA) targeting programmed death-ligand 1 and axitinib, VLN achieved to disrupt multiple immunosuppressive pathways and suppress the growth of melanoma in vivo. More importantly, VLN can co-deliver almost any combination of sgRNAs and small molecule drugs to tumors, suggesting the great potential of VLN as a general platform for the development of advanced combination therapies against malignant tumors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tumor heterogeneity has been one of the most important factors leading to the failure of conventional cancer therapies due to the accumulation of genetically distinct tumor-cell subpopulations during the tumor development process. Due to the diversity of genetic mutations during tumor growth, combining the use of multiple drugs has only achieved limited success in combating heterogeneous tumors. Herein, we report a novel antitumor strategy that effectively addresses tumor heterogeneity by using a CRISPR/Cas9-based nanoRNP carrying a combination of sgRNAs. Such nanoRNP is synthesized from Cas9 ribonucleoprotein, any combinations of required sgRNAs, and a rationally designed responsive polymer that endows nanoRNP with high circulating stability, enhanced tumor accumulation, and the efficient gene editing in targeted tumor cells eventually. By carrying a combination of sgRNAs that targets STAT3 and RUNX1, the nanoRNP exhibited efficient gene expression disruptions on a heterogeneous tumor model with two subsets of cells whose proliferations were sensitive to the reduced expression of STAT3 and RUNX1, respectively, leading to the effective growth inhibition of the heterogeneous tumor. Considering the close relationship between tumor heterogeneity and cancer progression, resistance to therapy, and recurrences, nanoRNP provides a feasible strategy to overcome tumor heterogeneity in the development of more advanced cancer therapy against malignant tumors.