A Quercetin/Rg3-Loaded Calcium Phosphate Nanoplatform Alleviates Breast Cancer-Induced Peripheral Hyperalgesia and...

This study aimed to develop a multifunctional nanoplatform, Rg3-Lip-CaPO₄/Quercetin (R-LCP/Q), for integrating antitumor therapy, immune modulation, and cancer pain relief.

R-LCP/Q was constructed by incorporating ginsenoside Rg3 into a lipid-coated calcium phosphate nanoplatform loaded with quercetin (Que). Its physicochemical properties, pH-responsive release, cellular uptake, antitumor activity, Ca²⁺-associated intracellular effects, immunogenic cell death (ICD), immune modulation, biodistribution, biosafety, and analgesic efficacy were evaluated in vitro and in a 4T1 breast cancer-associated pain model. The involvement of transient receptor potential vanilloid 1 (TRPV1) signalling in analgesia was further assessed using the selective TRPV1 antagonist AMG9810.

R-LCP/Q exhibited pH-responsive degradation and release of Ca²⁺, Que, and Rg3 under acidic conditions, together with enhanced cellular uptake and tumor-associated accumulation following Rg3 functionalization. R-LCP/Q induced intracellular Ca²⁺ accumulation, mitochondrial depolarization, ROS generation, and tumor-cell apoptosis; these effects were markedly attenuated by the intracellular Ca²⁺ chelator BAPTA, supporting a substantial Ca²⁺-dependent contribution to the cytotoxic response. R-LCP/Q also increased ICD-associated hallmarks and promoted dendritic cells (DCs) maturation. In vivo, R-LCP/Q suppressed tumor growth and was associated with enhanced DCs maturation, increased CD8⁺T-cell responses, a shift towards an M1-like macrophage phenotype, reduced regulatory T-cell frequencies, and decreased tumor-associated TNF-α and IL-6 levels. R-LCP/Q also alleviated mechanical and thermal hyperalgesia, accompanied by reduced TRPV1 expression in dorsal root ganglia and decreased serum substance P levels; pharmacological TRPV1 blockade with AMG9810 also produced an analgesic response. Short-term haematological, biochemical, histological, and haemocompatibility assessments indicated favourable tolerability.

R-LCP/Q provides preclinical proof of concept for a multifunctional nanotherapeutic strategy integrating tumor suppression, antitumor immune modulation, and cancer pain relief. The findings support further investigation of coordinated tumor-immune-nociceptive regulation as a therapeutic approach for cancer treatment.