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Nanocarriers have been widely employed to deliver chemotherapeutic drugs for cancer treatment. However, the insufficient accumulation of nanoparticles in tumors is an important reason for the poor efficacy of nanodrugs. In this study, a novel drug delivery system with a self-assembled amphiphilic peptide was designed to respond specifically to alkaline phosphatase (ALP), a protease overexpressed in cancer cells. The amphiphilic peptide self-assembled into spherical and fibrous nanostructures, and it easily assembled into spherical drug-loaded peptide nanoparticles after loading of a hydrophobic chemotherapeutic drug. The cytotoxicity of the drug carriers was enhanced against tumor cells over time. These spherical nanoparticles transformed into nanofibers under the induction of ALP, leading to efficient release of the encapsulated drug. This drug delivery strategy relying on responsiveness to an enzyme present in the tumor microenvironment can enhance local drug accumulation at the tumor site. The results of live animal imaging showed that the residence time of the morphologically transformable drug-loaded peptide nanoparticles at the tumor site was prolonged in vivo , confirming their potential use in antitumor therapy. These findings can contribute to a better understanding of the influence of drug carrier morphology on intracellular retention. [Display omitted] • Tumor microenvironment enzyme induced the geometrical shape switch of amphiphilic peptide VLKpY nanoparticles. • The obtained VLKpY nanoparticles were simple but smart with no modification. • The drug carriers displayed cytotoxic effects against tumor cells. • VLKpY nanoparticles enhanced the retention time in tumor cells. [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]