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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.)

The efficacy of chemotherapeutic drugs in tumor treatment is limited by their toxicity and side effects due to their inability to selectively accumulate in tumor tissue. In addition, chemotherapeutic agents are easily pumped out of tumor cells, resulting in their inadequate accumulation. To overcome these challenges, a drug delivery system utilizing the amphiphilic peptide Pep1 was designed. Pep1 can self-assemble into spherical nanoparticles (PL/Pep1) and encapsulate paclitaxel (PTX) and lapatinib (LAP). PL/Pep1 transformed into nanofibers in an acidic environment, resulting in longer drug retention and higher drug concentrations within tumor cells. Ultimately, PL/Pep1 inhibited tumor angiogenesis and enhanced tumor cell apoptosis. The use of shape-changing peptides as drug carriers to enhance cancer cell apoptosis is promising., 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.)

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.

The geometry of nanoparticles plays an important role in the process of drug encapsulation and release. In this study, an acid-responsive amphiphilic polypeptide consisting of lysine and leucine was prepared. In neutral media, the amphiphilic peptide L 6 K 4 self-assembled to form spherical nanoparticles and encapsulated fat-soluble antitumor drugs. The intratumoral accumulation of the drug-loaded nanoparticles was improved in HeLa cells compared with normal cells. Compared to a neutral environment, increasingly acidic solutions changed the secondary structure of the peptide. In addition, the drug-loaded nanoparticles expanded and decomposed, rapidly releasing the poorly soluble antitumor drug doxorubicin (DOX). In addition, the amphiphilic peptide L 6 K 4 had antitumor properties, and the antitumor performance of the combination of L 6 K 4 and DOX was better than that of free DOX. Our results indicate that the use of acid responsiveness to induce geometric changes in drug-loaded peptide nanoparticles could be a promising strategy for antitumor drug delivery.

Patients with cancer have reduced immune function and are susceptible to bacterial infection after surgery, chemotherapy, or radiotherapy. Spherical nanoparticles formed by the self-assembled peptide V 6 K 3 can be used as carriers for poorly soluble antitumor drugs to effectively deliver drugs into tumor cells. V 6 K 3 was designed to achieve nanoparticle-to-nanofiber geometric transformation under induction by plasma amine oxidase (PAO). PAO is commercially available and functionally similar to lysyl oxidase (LO), which is widely present in serum. After the addition of fetal bovine serum (FBS) or PAO, the secondary structure of the peptide changed, while the spherical nanoparticles stretched and transformed into nanofibers. The conversion of the self-assembled morphology reveals the susceptibility of this amphiphilic peptide to subtle chemical modifications and may lead to promising strategies to control self-assembled architecture via enzyme induction. Enzymatically self-assembled V 6 K 3 had bactericidal properties after PAO addition that were surprisingly superior to those before PAO addition, enabling this peptide to be used to prevent infection. The amphiphilic peptide V 6 K 3 displayed antitumor properties and low toxicity in mammalian cells, demonstrating good biocompatibility, as well as bactericidal properties, to prevent bacterial contamination. These advantages indicate that enzymatically self-assembled V 6 K 3 has great biomedical application potential in cancer therapy.

Amphiphilic peptides modified by molecular design can self-assemble into specific nanostructures with interesting applications in the fields of biomedicine and biotechnology. Lysyl oxidase (LO) is ubiquitous in human serum. However, enzymatic self-assembly of amphiphilic peptides remains a challenge for lipid-soluble drug delivery under the induction of LO. Here, we designed a positively charged amphiphilic peptide, A 6 K 2 , that could stably self-assemble to form nanovesicles. The lysine in the peptide molecule could be covalently cross-linked under enzyme catalysis, and the major transition was from random coil to β-sheet secondary structures, eventually leading to the destruction of the peptide nanovesicles. The lipid-soluble antitumour drug doxorubicin (DOX) as a model drug could be loaded into the hydrophobic core of the nanovesicles formed by the amphiphilic peptide A 6 K 2 , even though DOX was not covalently linked to the peptide monomer. The amount of DOX-encapsulated A 6 K 2 nanovesicles in human hepatocellular carcinoma BEL-7402 cells was significantly higher than that in human liver L02 cells, indicating excellent selectivity. The amphiphilic peptide A 6 K 2 inhibited tumour cell growth and had low cytotoxicity to mammalian cells, and it showed antibacterial activity against G + and G - bacteria. These advantages make enzymatic self-assembling A 6 K 2 nanovesicles of great interest in drug delivery for biomedical applications.

Hydrogels offer great potential for many biomedical and technological applications. For clinical uses, hydrogels that act as scaffold materials for cell culture, regenerative medicine, and drug delivery are required to have bactericidal properties. The amphiphilic peptide A9K2 was designed to effectively inhibit bacterial growth via a mechanism of membrane permeabilization. The present study demonstrated that addition of fetal bovine serum (FBS) or plasma amine oxidase (PAO) induced a sol-gel transition in A9K2 aqueous solutions. The transformation of A9K2 molecules catalyzed by lysyl oxidase (LO) in FBS or PAO accounted for the hydrogelation. Importantly, the enzymatic A9K2 hydrogel displayed high antibacterial ability against both Gram-negative and Gram-positive bacterial strains while showing extremely low mammalian cell cytotoxicity, thus demonstrating good biocompatibility. Under established coculture conditions, the peptide hydrogel showed excellent selectivity by favoring the adherence and spreading of mammalian cells, while killing pathogenic bacteria, thus avoiding bacterial contamination. These advantages endow the enzymatic A9K2 hydrogel with great potential for biomedical applications.

Conventional chemotherapeutic agents are limited by their lack of targeting and penetration and their short retention time, and chemotherapy might induce an immune suppressive environment. Peptide self‐assembly can result in a specific morphology, and the resulting morphological changes are stimuli responsive to the external environment, which is important for drug permeation and retention of encapsulated chemotherapeutic agents. In this study, a polypeptide (Pep1) containing the peptide sequences PLGLAG and RGD that is responsive to matrix metalloproteinase 2 (MMP‐2) was successfully developed. Pep1 underwent a morphological transformation from a spherical structure to aggregates with a high aspect ratio in response to MMP‐2 induction. This drug delivery system (DI/Pep1) can transport doxorubicin (DOX) and indomethacin (IND) simultaneously to target tumor cells for subsequent drug release while extending drug retention within tumor cells, which increases immunogenic cell death and facilitates the immunotherapeutic effect of CD4+ T cells. Ultimately, DI/Pep1 attenuated tumor‐associated inflammation, enhanced the body's immune response, and inhibited breast cancer growth by combining the actions of DOX and IND. Our research offers an approach to hopefully enhance the effectiveness of cancer treatment. [ABSTRACT FROM AUTHOR]

[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]

[Display omitted] • The deformable drug-loaded peptide nanocarriers PS/Pep1 achieved high penetration. • PS/Pep1 underwent morphological transformation to prolong the retention time of the encapsulated drugs. • In vivo and ex vivo experiments demonstrated that PS/Pep1 inhibits angiogenesis. • PS/pep1 can effectively inhibit tumor metastasis in vivo. Chemotherapeutic drugs have low aggregation rates and short retention times in tumors, severely limiting their clinical application. Additionally, the development and spread of solid tumors is highly dependent on neovascularization. An RGD-modified acid-responsive peptide was designed to encapsulate the chemotherapeutic drug paclitaxel (PTX) and the antiangiogenic drug sorafenib (SF), enabling them to self-assemble into nanoparticles (NPs) in a physiological environment. In an acidic environment, the release of PTX and SF was achieved when the drug-loaded experimental peptide PS/Pep1 transformed from spherical NPs into aggregates containing nanofibers, which effectively prolonged the retention of the encapsulated drug and increased drug accumulation. Furthermore, in vivo experiments provided compelling evidence of the strong inhibitory effects of PS/Pep1 on tumor growth and metastasis, as well as its effective suppression of angiogenesis. This targeted NP system that undergoes a morphological shift in the tumor microenvironment holds promise for enhancing the efficacy of the combined administration of chemotherapeutic and antiangiogenic drugs to inhibit tumor growth and metastasis. [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]