Self-assembled nanoparticle system synchronizing rapid analgesia and sustained anti-inflammatory therapy for inflammatory pain.

Inflammatory pain severely impacts patient well-being. Current treatments focus heavily on resolving inflammation yet often fail to offer rapid pain relief, leading to poor clinical compliance. To bridge this gap, we designed self-assembled nanoparticles that pair instant pain relief with long-term control of inflammation. The core consists of co-assembled lidocaine (LDC), capsaicin (CAP), and meloxicam (MLX) covered by a protective polyethylene glycol (PEG) shell. Upon reaching the weakly acidic inflammatory microenvironment, intermolecular interactions weaken, causing the drug to release rapidly. While local tissue acidity normally protonates LDC and blocks it from crossing nerve cell membranes, the co-released CAP specifically opens transient receptor potential vanilloid 1 (TRPV1) channels. This allows the protonated LDC to flow directly into neurons, securing rapid pain relief. Concurrently, MLX provides sustained anti-inflammatory action by blocking cyclooxygenase-2 (COX-2) and reducing prostaglandin E2 (PGE2) levels, along with other pro-inflammatory mediators. By syncing rapid nerve blockade with continuous anti-inflammatory action, this self-assembled nanosystem overcomes the pharmacokinetic mismatch in drug mixtures, offering a practical and highly effective strategy for inflammatory pain management.