Tumor microenvironment-oriented adaptive nanodrugs based on peptide self-assembly

The aberrant metabolism of tumor cells creates an inimitable microenvironment featuring acidic pH, high glutathione (GSH) levels, and overexpression of certain enzymes, which benefits the overwhelming progress of a tumor. Peptide self-assembly, emerging as a biofriendly and versatile fabrication strategy, harnesses multiple noncovalent interactions to obtain a variety of nanostructures tailored on demand. Orchestrating the reversible nature of noncovalent interactions and abnormal physiological parameters in the tumor microenvironment enables peptide-based nanodrugs to be targetable or switchable, thereby improving the drugs' bioavailability and optimizing the treatment outcome. This review will focus on peptide-modulated self-assembly of photosensitizers, chemotherapeutic drugs, immunoactive agents for tumor microenvironment-oriented adaptive phototherapy, chemotherapy, immunotherapy and combinatorial therapy. We will emphasize the building block design, the intermolecular interaction principle, adaptive structural transformation in the tumor microenvironment and corresponding therapeutic efficacy, and aim to elucidate the critical role of peptide-modulated, tumor microenvironment-oriented adaptive assemblies in improving the therapeutic index. Challenges and opportunities will be covered as well to advance the development and clinical application of tumor therapies based on peptide self-assembly materials and techniques. The tumor microenvironment is of significance to promote release or reorganization of peptide-modulated nanodrugs, optimizing drug bioavailability and therapeutic outcome.