Lymph node metastasis (LNM) significantly impacts disease staging, clinical management, and prognostic outcome [1], highlighting the importance of systematic lymph node resection as a standardized surgical procedure for cancer [2]. Moreover, residual tumor tissue and metastatic LNs are the leading causes of cancer relapse and metastasis after surgery[3], [4]. However, postoperative pathology confirms LNM in fewer than 20% of cancer patients, suggesting that nearly 80% undergo unnecessary lymphadenectomy [5]. Furthermore, LNs have been recognized as the key organ in immune response to cancer, particularly in the context of immunotherapy[6], [7], further supporting the potential benefits of non-surgical treatment strategies for LNs with tumor metastasis. Sentinel lymph node biopsy (SLNB) has been used as an alternative to lymphadenectomy in clinical practice for many solid tumors [8], while its application is limited by the poor targeting efficacy of the imaging agents (for instance, radioisotopes) and their associated toxicity [9]. Meanwhile, intraoperative frozen section pathology of LN is time-consuming and susceptible to diagnostic errors. In addition to the lack of rapid and accurate diagnosis, the treatment of LN metastasis is further limited by the inefficiency of drug delivery. Chemotherapy can suppress lymph node metastasis of tumors. However, systematically administered chemotherapeutics tend to accumulate in major organs and have limited access to the lymphatic system, significantly compromising their effectiveness against lymphatic metastases. Therefore, it remains a significant challenge to precise eliminate the residual tumors and selectively suppress the metastatic tumors in LNs for improving the clinical prognostic outcome following cancer surgery.
Leveraging the physiological structure of the lymphatic system, nanoparticles sized 10–100 nm are optimal for passive lymphatic uptake and LN targeting [10], [11]. Various lymphatic-targeted drug delivery nanocarriers have been developed to deliver therapeutics into LNs, including polymer-based micelle [12], cell membrane-derived nanoparticle [13], liposomes [14], mesoporous silica nanoparticles (MSN) [15], and the widely investigated lipid nanoparticles (LNPs) [16]. Nevertheless, the low targeting selectivity of nanocarriers between metastasis and normal LNs makes it difficult to distinguish metastatic lesions from healthy LN tissues. Moreover, the heterogeneity expression of receptors across tumors restricts the broad application of the delivery systems that rely on ligand-based active targeting nanoparticles [17]. These limitations greatly hinder their clinical application in the treatment of LN metastasis. Another major concern with chemotherapy is the serious toxicity and side effects caused by the undesired release of chemotherapeutic agents in healthy tissues. The physical encapsulation design of cancer nanotherapeutics in clinical use, such as Abraxane® and Doxil®, always leads to premature release of active drugs during bloodstream circulation, contributing to high toxicity and unsatisfactory anti-tumor outcomes [18], [19], [20]. Stimuli-responsive and pro-drug designs in smart nanomedicines enable tissue-specific and gate-controlled activation and release of medicine, thereby minimizing side effects and enabling precise cancer therapy [21], [22]. In recent years, we have developed an ultra-pH-sensitive (UPS) nanoplatform that leverages the acidic properties of the tumor microenvironment for precise cancer imaging [23], [24] and drug delivery [25], [26]. The UPS nanotechnology is based on ionizable amphiphilic block copolymers that exhibit an ultrasharp pH transition (∼ 0.2 pH units). This unique property enables the nanoparticles to remain stable under physiological conditions yet rapidly disassemble (within ∼2 ms) in the slightly acidic tumor microenvironment or endocytic organelles, accompanied by up to 100-fold signal amplification, thereby providing a powerful strategy for tumor-selective imaging and drug delivery. Based on the UPS nanotechnology, we have constructed a pH-amplified chemiluminescence resonance energy transfer (CRET) nanosensor (PCN) for noninvasive identification of tumor metastatic status in sentinel lymph nodes (SLNs) [27]. The self-illuminating luminol component in PCN can report the activity of myeloperoxidase (MPO), a biomarker of inflammatory phagocytes in metastatic SLNs [28]. Upon catalysis with MPO, luminol emits luminescence, which subsequently excites the near-infrared (NIR) fluorescent probe pyropheophorbide-a (PPa) via CRET, converting the luminescence into NIR light to indicate the occurrence of LN metastasis [29].
Herein, we design a self-illuminating and pH-MPO-ROS cascade-activatable prodrug nanoparticle (PCAPN) to further equip the PCN nanoprobe with therapeutic function for selectively eliminating the residual tumors and metastatic LNs after surgery (Fig. 1). The widely used chemotherapeutic agent, paclitaxel, is conjugated to the UPS polymer backbone via a reactive oxygen species (ROS)-responsive linkage, serving as the base drug unit. After specific activation and self-illuminating in tumor and metastatic LNs, the MPO-boosted PPa photosensitizer further generates ROS, enabling the in situ release of paclitaxel (PTX) for safe and effective treatment of cancer and metastatic LNs. This tri-gate design offers a promising and rational strategy for postoperative chemotherapy.