Engi­neer­ing Nanomed­i­cines for Tar­get­ed Neu­roim­mune Modulation

Tar­get­ed neu­ro-immune mod­u­la­tion offers a promis­ing strat­e­gy to coun­ter­act the pro­found immuno­sup­pres­sion char­ac­ter­is­tic of sol­id tumors. Although immune check­point inhibitors (ICI) have trans­formed can­cer ther­a­py, their effi­ca­cy remains lim­it­ed in tumors with high­ly sup­pres­sive microen­vi­ron­ments and is fre­quent­ly accom­pa­nied by immune-relat­ed tox­i­c­i­ties. Breast can­cer (BC), pan­cre­at­ic duc­tal ade­no­car­ci­no­ma (PDAC), and melanoma exem­pli­fy tumors in which restrict­ed immune-cell infil­tra­tion and potent immuno­sup­pres­sive cues hin­der ther­a­peu­tic success.

We present mul­ti­func­tion­al nanomed­i­cines designed to repro­gram the tumor microen­vi­ron­ment (TME) and poten­ti­ate ICI effi­ca­cy. These nanopar­ti­cles (NP) were ratio­nal­ly designed to tar­get den­drit­ic cells (DC) and key immuno­sup­pres­sive path­ways by incor­po­rat­ing tumor-asso­ci­at­ed anti­gens, TLR lig­ands (CpG and Poly(I:C)), and reg­u­la­tors of dom­i­nant sup­pres­sive medi­a­tors with­in the TME. Sur­face engi­neer­ing strate­gies enhanced DC acti­va­tion and improved NP traf­fick­ing and accu­mu­la­tion in tumors. Cy5.5‑labeled NP demon­strat­ed effi­cient in vivo inter­nal­iza­tion by DC and induced strong upreg­u­la­tion of co-stim­u­la­to­ry mol­e­cules (CD80, CD86, CD40) com­pared with non-car­bo­hy­drate carriers.

NP immune-mod­u­lat­ing and anti-tumor impact were val­i­dat­ed ex vivo using patient-derived organoids and in vivo across melanoma, PDAC, and BC mouse mod­els. Nanomed­i­cines elicit­ed potent anti­gen-spe­cif­ic immune respons­es, reshaped the immuno­log­i­cal pro­file of the TME, and sig­nif­i­cant­ly inhib­it­ed tumor pro­gres­sion. Syn­er­gis­tic ther­a­peu­tic ben­e­fits were observed when NP were com­bined with ICI, par­tic­u­lar­ly αOX40. In 4T1 and E0771 tumor-bear­ing mice, this com­bi­na­tion result­ed in marked tumor regres­sion and pro­longed survival.

In sum­ma­ry, the engi­neered nanomed­i­cine sys­tem effec­tive­ly repro­grams immune path­ways with­in the TME and sen­si­tizes sol­id tumors to immune check­point mod­u­la­tion, offer­ing a pow­er­ful strat­e­gy to enhance can­cer immunotherapy.