Phyto-Lipid Polymeric Hybrid Nanoparticles Enable Anti-inflammatory Immunomodulation through Corona-Mediated Cytokine Sequestration

Abstract Systemic inflammation and sepsis-associated cytokine storm remain major clinical challenges because current therapeutic strategies have limited ability to inhibit pre-established pro-inflammatory immune responses. Here, we report the engineering of a bioinspired phyto-lipid polymeric hybrid nanoparticle platform (PLPH-NP) that integrates maca-derived lipid NP (MDNP), isolated from Lepidium meyenii Walp., with immunomodulatory poly(lactic acid) (PLA) NP to attenuate systemic inflammation through complementary biomolecular corona-mediated cytokine sequestration and anti-inflammatory immunomodulatory mechanisms. PLPH-NP were fabricated by coating PLA NP cores with bioactive lipids isolated from MDNP through thin-film hydration and extrusion. Physicochemical characterization confirmed a distinct core–shell architecture with a zeta potential profile characteristic of the MDNP lipid interface, and particles remained colloidally stable under physiological conditions. In vitro studies using primary bone marrow-derived macrophages demonstrated efficient, time-dependent internalization of PLPH-NP and confirmed low cytotoxicity at therapeutically relevant concentrations. Functionally, PLPH-NP outperformed both MDNP and PLA NP individual controls, achieving superior suppression of LPS-induced NF-κB activation and significantly greater reductions in pro-inflammatory cytokine secretions. Cell-free sequestration assays further demonstrated that the hybrid architecture retained cytokine sequestration activity comparable to MDNP, confirming preservation of this key functional property, while PLA nanoparticles provided complementary suppression of innate immune signaling, together enabling a dual-action anti-inflammatory mechanism. In a murine LPS-induced endotoxemia rescue model, PLPH-NP efficiently suppressed IL-6, TNF-α, and IFN-β secretions in the plasma, while simultaneously mitigating inflammation-associated organ damage compared to controls. These results establish PLPH-NP as a modular, biologically inspired nanotherapeutic platform that addresses persistent barriers in immunomodulatory therapy for systemic inflammation.