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Increasing the penetration and accumulation of antitumor drugs at the tumor site are crucial in chemotherapy. Smaller drug-loaded nanoparticles (NPs) typically exhibit increased tumor penetration and more effective permeation through the nuclear membrane, whereas larger drug-loaded NPs show extended retention at the tumor site. In addition, cancer stem cells (CSCs) have unlimited proliferative potential and are crucial for the onset, progression, and metastasis of cancer. Therefore, a drug-loaded amphiphilic peptide, DDP- and ATRA-loaded Pep1 (DA/Pep1), is designed that self-assembles into spherical NPs upon the encapsulation of cis-diamminedichloroplatinum (DDP) and all-trans retinoic acid (ATRA). In an acidic environment, DA/Pep1 transforms into aggregates containing sheet-like structures, which significantly increases drug accumulation at the tumor site, thereby increasing antitumor effects and inhibiting metastasis. Moreover, although DDP treatment can increase the number of CSCs present, ATRA can induce the differentiation of CSCs in breast cancer to increase the therapeutic effect of DDP. In conclusion, this peptide nanodelivery system that transforms in response to the acidic tumor microenvironment is an extremely promising nanoplatform that suggests a new idea for the combined treatment of tumors., (© 2024 Wiley‐VCH GmbH.)

Immunotherapy is an emerging approach for the treatment of solid tumors. Although chemotherapy is generally considered immunosuppressive, specific chemotherapeutic agents can induce tumor immunity. In this study, we developed a targeted, acid-sensitive peptide nanoparticle (DT/Pep1) to deliver doxorubicin (DOX) and triptolide (TPL) to breast cancer cells via the enhanced permeability and retention (EPR) effect and the breast cancer-targeting effect of peptide D8. Compared with administration of the free drugs, treatment with the DT/Pep1 system increased the accumulation of DOX and TPL at the tumor site and achieved deeper penetration into the tumor tissue. In an acidic environment, DT/Pep1 transformed from spherical nanoparticles to aggregates with a high aspect ratio, which successfully extended the retention of the drugs in the tumor cells and bolstered the anticancer effect. In both in vivo and in vitro experiments, DT/Pep1 effectively blocked the cell cycle and induced apoptosis. Importantly, the DT/Pep1 system efficiently suppressed tumor development in mice bearing 4T1 tumors while simultaneously promoting immune system activation. Thus, the results of this study provide a system for breast cancer therapy and offer a novel and promising platform for peptide nanocarrier-based drug delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.

[Display omitted] • The deformable drug-loaded peptide nanocarriers DM/Pep1 targeted breast cancer cells. • DM/Pep1 underwent morphological transformation to prolong the retention time of the encapsulated drugs. • DM/Pep1 upregulated CD4, induced calreticulin exposure, downregulated PD-L1 and enhanced antitumor immune response. Insufficient drug accumulation at tumor sites is one of the key factors leading to treatment failure in breast cancer (BC), and developing a chemotherapeutic drug delivery system that can improve the immune microenvironment to expand the benefits of immunochemotherapy for BC remains a challenge. To increase the efficacy of BC treatment by extending drug retention at the tumor site, we developed a pH-responsive peptide modified with the PHSCN peptide sequence (Pep1) that self-assembles to form spherical DM/Pep1 nanoparticles after encapsulating doxorubicin (DOX) and metformin (MET). In the acidic tumor microenvironment, spherical nanocarriers transform into aggregates with a high aspect ratio, facilitating DOX and MET release for combined chemotherapy and immunomodulation. In cellular experiments, this construct provided prolonged drug retention in BC cells. In a subcutaneous tumor mouse model, the DM/Pep1 nanoparticles exhibited a superior tumor inhibition effect compared to that of free DOX/MET. The DM/Pep1 nanocomplex upregulated CD4, induced calreticulin (CRT) exposure, downregulated PD-L1, and enhanced the MET-mediated antitumor immune response. The use of this pH-responsive peptide nanocarrier system with morphological transformation offers a promising strategy for BC therapy. [ABSTRACT FROM AUTHOR]

• DOX/IpYR achieved high penetration and long-term retention simultaneously. • DOX/IpYR regulated the expression of immune factors and PD-L1. • DOX/IpYR suppressed tumour growth and metastases. Conventional intratumoural drug delivery systems often struggle to achieve both high permeability and long-term retention. Smaller nanoparticles (NPs) readily diffuse into deep tumour regions, but their rapid clearance results in lower accumulation at tumour sites. Furthermore, although immunostimulatory molecules have been introduced for the immunotherapy of tumours, it is crucial to develop drug nanovehicles with immunomodulatory functions. Here, a novel self-assembled amphiphilic peptide, IpYR, self-assembled into spherical NPs after drug loading, which were transformed into nanofibres (NFs) with a high aspect ratio under the induction of alkaline phosphatase (ALP). This drug-loading system effectively prolonged the residence time of the chemotherapeutic drug in tumour tissues and displayed enhanced aggregation at tumour sites in vivo. Furthermore, the transformable peptide NPs not only inhibited tumour growth but also suppressed tumour metastasis. Importantly, the peptide nanovehicles inhibited the proliferation of Treg cells, downregulated the expression of immunosuppressive factors and PD-L1, and simultaneously stimulated the expression of immunogenic factors, effectively alleviating the immunosuppressive microenvironment. In conclusion, this transformable peptide-based nanodelivery system is a concise and promising nanoplatform for maintaining potent drug enrichment and inhibiting immunosuppression in the tumour microenvironment. [ABSTRACT FROM AUTHOR]