Fibrin-targeted photosensitizer aggregates significantly enhance the delivery of chemotherapeutic drugs to tumor vasculature.

Current drug carriers, while effective in mitigating therapeutic side effects, frequently elicit non-drug-related adverse reactions, including hepatorenal toxicity, oxidative stress and allergic responses. To address these issues and enhance drug efficacy, we propose a "drug-carrying-drug" strategy that integrates photodynamic therapy (PDT) with chemotherapy for potential tumor eradication. Traditional photosensitizers often confront a paradoxical dilemma between aggregation-induced photodynamic deactivation and dispersion-mediated premature photobleaching. To overcome these limitations, we developed PPCNM, a multifunctional micellar carrier. PPCNM is constructed by PEGylating pyropheophorbide-α (PPA), a porphyrin-based photosensitizer, and conjugating it with the tumor-targeting pentapeptide CREKA. Before entering tumor cells, PPCNM remains aggregated to prevent photobleaching. Upon internalization, it disassembles to activate PDT and stably delivers doxorubicin (DOX). DOX@PPCNM not only mitigates photobleaching and phototoxicity caused by premature PDT activation but also alleviates adverse effects associated with chemotherapeutic monotherapy. The fibrin- specific CREKA peptide, which targets tumor vasculature, improves the precise delivery of photosensitizers and chemotherapeutics to tumor tissues. Overall, this study presents a promising strategy for developing a dual-drug targeted delivery system combining PDT with other therapies.