<p>Photodynamic therapy (PDT) has emerged as an advanced therapeutic modality owing to its inherent merits of minimal invasiveness and precise spatiotemporal control. However, its clinical translation is hampered by limitations of conventional photosensitizers (PSs), including poor aqueous solubility, weak absorption within the 650–800&#xa0;nm phototherapeutic window (PTW), and inadequate tumor targeting. As a unique natural perylenequinone-based PS endemic to China, hypocrellin exhibits exceptional photophysical properties, such as strong absorption in the visible region and a high singlet oxygen (¹O₂) quantum yield. Nevertheless, its hydrophobicity and insufficient PTW absorption severely hamper biomedical applications. In recent years, rational modification and nanodelivery engineering have enhanced the aqueous solubility, biocompatibility, and tumor-targeting capability of hypocrellin. Particularly, tailoring surface modifications to redshift absorption to the near-infrared-PTW enables hypocrellin-based nanoplatforms integrated with multimodal synergistic therapies, including PDT, sonodynamic therapy (SDT), chemotherapy, and photothermal therapy (PTT). These nanoplatforms leverage the pathological microenvironment hallmarks to amplify efficacy via synergistic effects. This review summarizes the photodynamic mechanism of hypocrellin, surface modification strategies, and nanodelivery design. Special emphasis is placed on recent advances in spectral regulation and solubility enhancement, along with its applications in antitumor, antibacterial, antiviral, anti-inflammatory, and multimodal therapies. Furthermore, we provide an in-depth analysis of strategies to circumvent tumor hypoxic microenvironment and biosafety challenges of hypocrellin-based nanocarriers. Finally, the development of stimuli-responsive delivery systems is prospected, aiming to provide critical insights for clinical translation of this natural PS.</p> Graphical abstract <p></p>